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1

Human gene therapy and imaging in neurological diseases  

PubMed Central

Molecular imaging aims to assess non-invasively disease-specific biological and molecular processes in animal models and humans in vivo. Apart from precise anatomical localisation and quantification, the most intriguing advantage of such imaging is the opportunity it provides to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Further, molecular imaging can be used to address basic scientific questions, e.g. transcriptional regulation, signal transduction or protein/protein interaction, and will be essential in developing treatment strategies based on gene therapy. Most importantly, molecular imaging is a key technology in translational research, helping to develop experimental protocols which may later be applied to human patients. Over the past 20 years, imaging based on positron emission tomography (PET) and magnetic resonance imaging (MRI) has been employed for the assessment and “phenotyping” of various neurological diseases, including cerebral ischaemia, neurodegeneration and brain gliomas. While in the past neuro-anatomical studies had to be performed post mortem, molecular imaging has ushered in the era of in vivo functional neuro-anatomy by allowing neuroscience to image structure, function, metabolism and molecular processes of the central nervous system in vivo in both health and disease. Recently, PET and MRI have been successfully utilised together in the non-invasive assessment of gene transfer and gene therapy in humans. To assess the efficiency of gene transfer, the same markers are being used in animals and humans, and have been applied for phenotyping human disease. Here, we review the imaging hallmarks of focal and disseminated neurological diseases, such as cerebral ischaemia, neurodegeneration and glioblastoma multiforme, as well as the attempts to translate gene therapy’s experimental knowledge into clinical applications and the way in which this process is being promoted through the use of novel imaging approaches. PMID:16328505

Jacobs, Andreas H.; Winkler, Alexandra; Castro, Maria G.; Lowenstein, Pedro

2010-01-01

2

Molecular Imaging-guided Gene Therapy of Gliomas  

Microsoft Academic Search

Gene therapy of patients with glioblastoma using viral and non-viral vectors, which are applied by direct injection or convection-enhanced\\u000a delivery (CED), appear to be satisfactorily safe. Up to date, only single patients show a significant therapeutic benefit\\u000a as deduced from single long-term survivors. Non-invasive imaging by PET for the identification of viable target tissue and\\u000a for assessment of transduction efficiency

Maria A. Rueger; Alexandra Winkeler; Anne V. Thomas; Lutz W. Kracht; Andreas H. Jacobs

3

Genes and Gene Therapy  

MedlinePLUS

... a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

4

The Application of Nanoparticles in Gene Therapy and Magnetic Resonance Imaging  

PubMed Central

The combination of nanoparticles, gene therapy, and medical imaging has given rise to a new field known as gene theranostics, in which a nanobioconjugate is used to diagnose and treat the disease. The process generally involves binding between a vector carrying the genetic information and a nanoparticle, which provides the signal for imaging. The synthesis of this probe generates a synergic effect, enhancing the efficiency of gene transduction and imaging contrast. We discuss the latest approaches in the synthesis of nanoparticles for magnetic resonance imaging, gene therapy strategies, and their conjugation and in vivo application. PMID:21484943

HERRANZ, FERNANDO; ALMARZA, ELENA; RODRÍGUEZ, IGNACIO; SALINAS, BEATRIZ; ROSELL, YAMILKA; DESCO, MANUEL; BULTE, JEFF W.; RUIZ-CABELLO, JESÚS

2012-01-01

5

[Gene therapy].  

PubMed

In the last years there has been much progress in our understanding of molecular mechanisms in the pathogenesis of disease. In this review we provide an overview of gene therapy, its most actualized techniques for gene delivery, and we give specific examples of laboratory and clinical achievements to date. The development of methods for delivering genes to mammalian cells has stimulated great interest in the possibility of treating human disease by gene-based therapies. As a result, concepts and methods that would have been considered purely science fiction 50 years ago are now used in the treatment of diseases. The widespread application of gene therapy technology to many diseases is already breaking down the traditional boundaries of modern medicine. However, despite its progress, several key technical drawbacks need to be overcome before gene therapy can be used safely and effectively in clinical settings. Technological developments, particularly in the areas of gene delivery and cell transplantation, will be critical for the successful practice of gene therapy. PMID:9527700

Rodríguez-Fragoso, L

1997-01-01

6

MRI-guided gene therapy Xiaoming Yanga  

E-print Network

Minireview MRI-guided gene therapy Xiaoming Yanga , Ergin Atalara,b,* a Department of Radiology gene expression. This review summarizes the current status of MRI- guided gene therapy. Ã? 2006 resonance imaging; MRI-guided therapy; Gene therapy 1. Introduction Gene therapy is an exciting frontier

Atalar, Ergin

7

Noninvasive imaging of hypoxia-inducible factor-1? gene therapy for myocardial ischemia.  

PubMed

Hypoxia-inducible factor-1 alpha (HIF-1?) gene therapy holds great promise for the treatment of myocardial ischemia. Both preclinical and clinical evaluations of this therapy are underway and can benefit from a vector strategy that allows noninvasive assessment of HIF-1? expression as an objective measure of gene delivery. We have developed a novel bidirectional plasmid vector (pcTnT-HIF-1?-VP2-TSTA-fluc), which employs the cardiac troponin T (cTnT) promoter in conjunction with a two-step transcriptional amplification (TSTA) system to drive the linked expression of a recombinant HIF-1? gene (HIF-1?-VP2) and the firefly luciferase gene (fluc). The firefly luciferase (FLuc) activity serves as a surrogate for HIF-1?-VP2 expression, and can be noninvasively assessed in mice using bioluminescence imaging after vector delivery. Transfection of cultured HL-1 cardiomyocytes with pcTnT-HIF-1?-VP2-TSTA-fluc led to a strong correlation between FLuc and HIF-1?-dependent vascular endothelial growth factor expression (r(2)=0.88). Intramyocardial delivery of pcTnT-HIF-1?-VP2-TSTA-fluc into infarcted mouse myocardium led to persistent HIF-1?-VP2 expression for 4 weeks, even though it improved neither CD31+ microvessel density nor echocardiographically determined left ventricular systolic function. These results lend support to recent findings of suboptimal efficacy associated with plasmid-mediated HIF-1? therapy. The imaging techniques developed herein should be useful for further optimizing HIF-1?-VP2 therapy in preclinical models of myocardial ischemia. PMID:23937265

Chen, Ian Y; Gheysens, Olivier; Li, Zongjin; Rasooly, Julia A; Wang, Qian; Paulmurugan, Ramasamy; Rosenberg, Jarrett; Rodriguez-Porcel, Martin; Willmann, Juergen K; Wang, David S; Contag, Christopher H; Robbins, Robert C; Wu, Joseph C; Gambhir, Sanjiv S

2013-10-01

8

Cochlear Gene Therapy  

PubMed Central

The purpose of this review is to highlight recent advances in cochlear gene therapy over the past several years. Cochlear gene therapy has undergone tremendous advances over the past decade. Beginning with some groundbreaking work in 2005 documenting hair cell regeneration using virallymediated delivery of the mouse atonal 1 gene, gene therapy is now being explored as a possible treatment for a variety of causes of hearing loss. Recent advances in cochlear gene therapy include improved methods of gene delivery with a better delineation of viral vectors that are suitable for this purpose, additional improvements in hair cell regeneration, and directed research towards autoimmune hearing loss, ototoxicity, spiral ganglion survival, and genetic forms of hearing loss. If successful, cochlear gene therapy will dramatically alter our ability to treat a variety of forms of acquired and genetic hearing loss. PMID:22157110

Lustig, Lawrence R.; Akil, Omar

2013-01-01

9

Cancer gene therapy  

E-print Network

Cancer gene therapy can be defined as transfer of nucleic acids into tumor or normal cells with aim to eradicate or reduce tumor mass by direct killing of cells, immunomodulation or correction of genetic errors, and reversion of malignant status. Initially started with lots of optimism and enthusiasm, cancer gene therapy has shown limited success in treatment of patients. This review highlights current limitations and almost endless possibilities of cancer gene therapy. The major difficulty in advancing gene therapy technology from the bench to the clinical practice is problem with gene delivery vehicles (so called vectors) needed to ferry genetic material into a cell. Despite few reports of therapeutic responses in some patients, there is still no proof of clinical efficacy of most cancer gene therapy approaches, primarily due to very low transduction and expression efficacy in vivo of available vectors. An ãidealÒ gene therapy vector should be administrated through a noninvasive route and should be targeted not only to primary tumor mass but also to disseminated tumor cells and micrometastases; it should also carry therapeutic gene with tumor-restricted, time-regulated, and sustained expression. Current strategies for combating the cancer with gene therapy can be divided into four basic concepts: (1) replacement of missing tumor suppressor gene and/or blocking of oncogenes or pro-inflammatory genes, (2)

Arch Oncol; Tatjana Mitroviæ

10

Noninvasive optical imaging of nitroreductase gene-directed enzyme prodrug therapy system in living animals  

Microsoft Academic Search

Gene-directed enzyme prodrug therapy (GDEPT) is a promising and emerging strategy that attempts to limit the systemic toxicity inherent to cancer chemotherapy by means of tumor-targeted delivery and expression of an exogenous gene whose product converts nontoxic prodrug(s) into activated cytotoxic agent(s). The bacterial nitroreductase (NTR) enzyme, coupled with its substrate prodrug 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954), is a promising GDEPT strategy that

S Bhaumik; T V Sekar; J Depuy; J Klimash; R Paulmurugan

2012-01-01

11

Molecular Imaging of Biological Gene Delivery Vehicles for Targeted Cancer Therapy: Beyond Viral Vectors  

Microsoft Academic Search

Cancer persists as one of the most devastating diseases in the world. Problems including metastasis and tumor resistance to\\u000a chemotherapy and radiotherapy have seriously limited the therapeutic effects of present clinical treatments. To overcome these\\u000a limitations, cancer gene therapy has been developed over the last two decades for a broad spectrum of applications, from gene\\u000a replacement and knockdown to vaccination,

Jung-Joon Min; Vu H. Nguyen; Sanjiv S. Gambhir

2010-01-01

12

The use of high-frequency ultrasound imaging and biofluorescence for in vivo evaluation of gene therapy vectors  

PubMed Central

Background Non-invasive imaging of the biodistribution of novel therapeutics including gene therapy vectors in animal models is essential. Methods This study assessed the utility of high-frequency ultrasound (HF-US) combined with biofluoresence imaging (BFI) to determine the longitudinal impact of a Herpesvirus saimiri amplicon on human colorectal cancer xenograft growth. Results HF-US imaging of xenografts resulted in an accurate and informative xenograft volume in a longitudinal study. The volumes correlated better with final ex vivo volume than mechanical callipers (R2 = 0.7993, p = 0.0002 vs. R2 = 0.7867, p = 0.0014). HF-US showed that the amplicon caused lobe formation. BFI demonstrated retention and expression of the amplicon in the xenografts and quantitation of the fluorescence levels also correlated with tumour volumes. Conclusions The use of multi-modal imaging provided useful and enhanced insights into the behaviour of gene therapy vectors in vivo in real-time. These relatively inexpensive technologies are easy to incorporate into pre-clinical studies. PMID:24219244

2013-01-01

13

Sodium Iodide Symporter for Nuclear Molecular Imaging and Gene Therapy: From Bedside to Bench and Back  

PubMed Central

Molecular imaging, defined as the visual representation, characterization and quantification of biological processes at the cellular and subcellular levels within intact living organisms, can be obtained by various imaging technologies, including nuclear imaging methods. Imaging of normal thyroid tissue and differentiated thyroid cancer, and treatment of thyroid cancer with radioiodine rely on the expression of the sodium iodide symporter (NIS) in these cells. NIS is an intrinsic membrane protein with 13 transmembrane domains and it takes up iodide into the cytosol from the extracellular fluid. By transferring NIS function to various cells via gene transfer, the cells can be visualized with gamma or positron emitting radioisotopes such as Tc-99m, I-123, I-131, I-124 and F-18 tetrafluoroborate, which are accumulated by NIS. They can also be treated with beta- or alpha-emitting radionuclides, such as I-131, Re-186, Re-188 and At-211, which are also accumulated by NIS. This article demonstrates the diagnostic and therapeutic applications of NIS as a radionuclide-based reporter gene for trafficking cells and a therapeutic gene for treating cancers. PMID:22539935

Ahn, Byeong-Cheol

2012-01-01

14

Bispecific Antibodies and Gene Therapy  

Microsoft Academic Search

\\u000a Gene therapy is the transfer of therapeutic genes, via gene transfer vectors, into patients for therapeutic purposes. Different\\u000a gene therapy strategies are being pursued, including long-term gene correction of monogenetic diseases, eradication of tumor\\u000a cells in cancer patients, or genetic vaccination for infectious diseases. Bispecific antibodies and gene therapy are connected\\u000a in two ways. First, bispecific antibodies are tools of

Dirk M. Nettelbeck

15

Therapeutic genes for cancer gene therapy  

Microsoft Academic Search

Cancer still represents a disease of high incidence and is therefore one major target for gene therapy approaches. Gene therapy\\u000a for cancer implies that ideally selective tumor cell killing or inhibition of tumor cell growth can be achieved using nucleic\\u000a acids (DNA and RNA) as the therapeutic agent. Therefore, the majority of cancer gene therapy strategies introduce foreign\\u000a genes into

Wolfgang Walther; Ulrike Stein

1999-01-01

16

Genetics Home Reference: What is gene therapy?  

MedlinePLUS

... Genomic Research Next Handbook > Gene Therapy > What is gene therapy? Gene therapy is an experimental technique that ... have no other cures. For general information about gene therapy: MedlinePlus from the National Library of Medicine ...

17

Experimental Study of Nasopharyngeal Carcinoma Radionuclide Imaging and Therapy Using Transferred Human Sodium/Iodide Symporter Gene  

PubMed Central

Purpose The aim of this study was to design a method of radionuclide for imaging and therapy of nasopharyngeal carcinoma (NPC) using the transferred human sodium/iodide symporter (hNIS) gene. Methods A stable NPC cell line expressing hNIS was established (CNE-2-hNIS). After 131I treatment, we detected proliferation and apoptosis of NPC cells, both in vitro and vivo. In vivo, the radioactivity of different organs of nude mice was counted and 99mTc imaging using SPECT was performed. The apparent diffusion coefficient (ADC) value changes of tumor xenografts were observed by diffusion-weighted magnetic resonance imaging (DW-MRI) within 6–24 days of 131I treatment. The correlation of ADC changes with apoptosis and proliferation was investigated. Post-treatment expression levels of P53, Bax, Bcl-2, Caspase-3, and Survivin proteins were detected by western blotting. Results 131I uptake was higher in CNE-2-hNIS than in CNE-2 cells. The proliferation and apoptosis rate decreased and increased respectively both in vitro and vivo in the experimental group after 131I treatment. The experimental group tumors accumulated 99mTc in vivo, leading to a good visualization by SPECT. DW-MRI showed that ADC values increased in the experimental group 6 days after treatment, while ADC values were positively and negatively correlated with the apoptotic and Ki-67 proliferation indices, respectively. After treatment, CNE-2-hNIS cells up-regulated the expression of P53 and Survivin proteins and activated Caspase-3, and down-regulated the expression of Bcl-2 proteins. Conclusions The radionuclide imaging and therapy technique for NPC hNIS-transfected cell lines can provide a new therapy strategy for monitoring and treatment of NPC. PMID:25615643

Zhong, Xing; Shi, Changzheng; Gong, Jian; Guo, Bin; Li, Mingzhu; Xu, Hao

2015-01-01

18

Noninvasive Imaging of Herpes Virus Thymidine Kinase Gene Transfer and Expression: A Potential Method for Monitoring Clinical Gene Therapy  

Microsoft Academic Search

Noninvasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk)gene expression is possible with a clinical gamma camera and by single-photon emission tomography (SPECT) using ‘3t1-labeled 2'- ftuo@2'deoxy-1-@-D-arabinofuranosyl-5-iodo-uradil (FIAU). Studies were performed in rats bearing s.c. tumors. Tumors were produced by injection of wild-typeRG2gliomaor W256mammary carcinomacells into one flank and RG2TK+ glioma or W256TK+ mammary carcinoma cells (that had

Jun G. TJuvajev; Ronald Finn; Kyoichi Watanabe; Revathi Joshi; Takamitsu Oku; John Kennedy; Bradley Beattie; Jason Koutcher; Steven Larson; Ronald G. Blasberg

19

Gene Therapy and Children (For Parents)  

MedlinePLUS

... that don't respond to conventional therapies. About Genes Our genes help make us unique. Inherited from ... by a "bad" gene. Continue Two Types of Gene Therapy The two forms of gene therapy are: ...

20

Gene therapy in diabetes  

PubMed Central

Type 1 diabetes (T1D) is a chronic autoimmune disease, whereby auto-reactive cytotoxic T cells target and destroy insulin-secreting ?-cells in pancreatic islets leading to insulin deficiency and subsequent hyperglycemia. These individuals require multiple daily insulin injections every day of their life without which they will develop life-threatening diabetic ketoacidosis (DKA) and die. Gene therapy by viral vector and non-viral transduction may be useful techniques to treat T1D as it can be applied from many different angles; such as the suppression of autoreactive T cells to prevent islet destruction (prophylactic) or the replacement of the insulin gene (post-disease). The need for a better method for providing euglycemia arose from insufficient numbers of cadaver islets for transplantation and the immunosuppression required post-transplant. Ectopic expression of insulin or islet modification have been examined, but not perfected. This review examines the various gene transfer methods, gene therapy techniques used to date and promising novel techniques for the maintenance of euglycemia in the treatment of T1D. PMID:21487475

Wong, Mary S; Hawthorne, Wayne J

2010-01-01

21

Advances in Preclinical Investigation of Prostate Cancer Gene Therapy  

E-print Network

Advances in Preclinical Investigation of Prostate Cancer Gene Therapy Marxa L Figueiredo1 efforts in the last decade have shown that adenoviral vector-based gene therapy is a promising approach vectors, therapy coupled to reporter gene imaging, and com- bined treatment modalities. In fact, the early

Cai, Long

22

original article The American Society of Gene & Cell Therapy Molecular Therapy 1  

E-print Network

original article© The American Society of Gene & Cell Therapy Molecular Therapy 1 The transfection a critical impediment to successful clinical translation of gene therapy. Polyplexes formed by combining DNA decondensation/unpacking kinetics. Major barriers to nonviral gene transfer were studied by image

Buschmann, Michael

23

Local Gene Therapy for Cancer  

Microsoft Academic Search

Cancer is an important problem in public health worldwide. Gene therapy has the potential for improved treatment of cancer\\u000a patients, particularly if used in combination with other, conventional therapies. To date, many strategies of gene therapy\\u000a have been explored, including correction of mutant genes, immunstimulation, prodrug activation, interference of oncogene expression,\\u000a and genetically modified oncolytic viruses. Although the preclinical results

Wolfgang Walther; Ulrike S. Stein; Peter M. Schlag

24

Human Gene Therapy: Genes without Frontiers?  

ERIC Educational Resources Information Center

Describes the latest advancements and setbacks in human gene therapy to provide reference material for biology teachers to use in their science classes. Focuses on basic concepts such as recombinant DNA technology, and provides examples of human gene therapy such as severe combined immunodeficiency syndrome, familial hypercholesterolemia, and…

Simon, Eric J.

2002-01-01

25

Non-invasive in vivo imaging with radiolabelled FIAU for monitoring cancer gene therapy using herpes simplex virus type 1 thymidine kinase and ganciclovir  

Microsoft Academic Search

An experimental cancer gene therapy model was employed to develop a non-invasive imaging procedure using radiolabelled 2'-fluoro-2'-deoxy-5-iodo-1-ß-d-arabinofuranosyluracil (FIAU) as an enzyme substrate for monitoring retroviral vector-mediated herpes simplex virus type 1 thymidine kinase gene ( HSV1-tk) transgene expression. Iodine-131 labelled FIAU was prepared by a no-carrier-added (n.c.a.) synthesis process and lyophilised to give \\

Win-Ping Deng; Wen K. Yang; Wen-Fu Lai; Ren-Shyan Liu; Jeng-Jong Hwang; Den-Mei Yang; Ying-Kai Fu; Hsin-Ell Wang

2004-01-01

26

Gene therapy for lung cancer.  

PubMed

Over the past three decades, the molecular biology of lung cancer has been progressively delineated. Concurrently, gene therapy techniques have been developed that allow targeting or replacement of dysfunctional genes in cancer cells, such as activated tumor-promoting oncogenes, inactivated tumor-suppressing, or apoptosis-promoting genes. This article will review the therapeutic implications of molecular changes associated with non-small cell lung cancer and the status of gene therapy. PMID:16253824

Toloza, Eric M

2005-01-01

27

Optical image-guided cancer therapy.  

PubMed

Optical molecular imaging holds great promise for image guiding cancer therapy. The non-invasive guidance of therapeutic strategies would enable the removal of cancerous tissue while avoiding side effects and systemic toxicity, preventing damage of healthy tissues and decreasing the risk of postoperative problems. This review article highlights the advantages and disadvantages of the optical imaging techniques that are currently available, including their recent applications in image-guided cancer therapy. Three approaches for optical image-guided cancer therapy were discussed in this review, namely, bioluminescence imaging (BLI), fluorescence imaging (FI) and Cerenkov luminescence imaging (CLI). BLI is always used in small animal imaging for the in vivo tracking of therapeutic gene expression and cell-based therapy. To the contrary, FI display high promising for clinical translation. The applications of FI include image-guided surgery, radiotherapy, gene therapy, drug delivery and sentinel lymph node fluorescence mapping. CLI is a novel radioactive optical hybrid imaging strategy and its use for animal and clinical translation was also discussed. Perspectives on the translation of optical image-guided cancer therapy into clinical practice were provided. PMID:24372233

Bu, Lihong; Ma, Xiaowei; Tu, Yingfeng; Shen, Baozhong; Cheng, Zhen

2013-01-01

28

Gene therapy for hemophilia.  

PubMed

Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors. PMID:25553466

Rogers, Geoffrey L; Herzog, Roland W

2015-01-01

29

Gene therapy for Deafness  

PubMed Central

Hearing loss is the most common sensory deficit in humans and can result from genetic, environmental, or combined etiologies that prevent normal function of the cochlea, the peripheral sensory organ. Recent advances in understanding the genetic pathways that are critical for the development and maintenance of cochlear function, as well as the molecular mechanisms that underlie cell trauma and death have provided exciting opportunities for modulating these pathways to correct genetic mutations, to enhance endogenous protective pathways for hearing preservation and to regenerate lost sensory cells with the possibility of ameliorating hearing loss. A number of recent animal studies have used gene-based therapies in innovative ways toward realizing these goals. With further refinement, some of the protective and regenerative approaches reviewed here may become clinically applicable. PMID:23864018

Kohrman, David C.; Raphael, Yehoash

2014-01-01

30

Gene Therapy for Diseases and Genetic Disorders  

MedlinePLUS

Gene Therapy for Diseases Gene Therapy has made important medical advances in less than two decades. Within ... Among the most notable advancements are the following: Gene Therapy for Genetic Disorders Severe Combined Immune Deficiency ( ...

31

What is Gene Therapy? Rafael Yez  

E-print Network

What is Gene Therapy? Rafael Yáñez rafael.yanez@rhul.ac.uk Rare Disease Day @ Royal Holloway 28th therapy strategies: "random" integration transgene transgene * #12;Gene Therapy successes;Gene therapy strategies: episomal vectors transgene transgene * #12;DNA repair #12;Gene therapy

Royal Holloway, University of London

32

A dual function fusion protein of Herpes simplex virus type 1 thymidine kinase and firefly luciferase for noninvasive in vivo imaging of gene therapy in malignant glioma  

PubMed Central

Background Suicide gene therapy employing the prodrug activating system Herpes simplex virus type 1 thymidine kinase (HSV-TK)/ ganciclovir (GCV) has proven to be effective in killing experimental brain tumors. In contrast, glioma patients treated with HSV-TK/ GCV did not show significant treatment benefit, most likely due to insufficient transgene delivery to tumor cells. Therefore, this study aimed at developing a strategy for real-time noninvasive in vivo monitoring of the activity of a therapeutic gene in brain tumor cells. Methods The HSV-TK gene was fused to the firefly luciferase (Luc) gene and the fusion construct HSV-TK-Luc was expressed in U87MG human malignant glioma cells. Nude mice with subcutaneous gliomas stably expressing HSV-TK-Luc were subjected to GCV treatment and tumor response to therapy was monitored in vivo by serial bioluminescence imaging. Bioluminescent signals over time were compared with tumor volumes determined by caliper. Results Transient and stable expression of the HSV-TK-Luc fusion protein in U87MG glioma cells demonstrated close correlation of both enzyme activities. Serial optical imaging of tumor bearing mice detected in all cases GCV induced death of tumor cells expressing the fusion protein and proved that bioluminescence can be reliably used for repetitive and noninvasive quantification of HSV-TK/ GCV mediated cell kill in vivo. Conclusion This approach may represent a valuable tool for the in vivo evaluation of gene therapy strategies for treatment of malignant disease. PMID:15294018

Söling, Ariane; Theiß, Christian; Jungmichel, Stephanie; Rainov, Nikolai G

2004-01-01

33

Relationship between Apoptosis Imaging and Radioiodine Therapy in Tumor Cells with Different Sodium Iodide Symporter Gene Expression.  

PubMed

AbstractThe therapeutic efficacy of radioiodine (131I) therapy has been reported to be variable among cancer patients and even between metastatic regions in the same patients. Because the expression level of sodium iodide symporter (NIS) cannot reflect the efficacy of therapy, other strategies are required to predict the precise therapeutic effect of 131I therapy. In this research, we investigated the correlation between iodine (I) uptake, apoptosis imaging, and therapeutic efficacy. Two HT29 cell lines, cytomegalovirus (CMV)-NIS (or NIS+++) and TERT-NIS (or NIS+), were established by retroviral transfection. I uptake was estimated by I-uptake assay and gamma camera imaging. Apoptosis was evaluated by confocal microscopy and a Maestro fluorescence imaging system (CRi Inc., Woburn, MA) using ApoFlamma (BioACTs, Seoul, Korea), a fluorescent dye-conjugated apoptosis-targeting peptide 1 (ApoPep-1). Therapeutic efficacy was determined by tumor size. The CMV-NIS showed higher I uptake and ApoFlamma signals than TERT-NIS. In xenograft models, CMV-NIS also showed high 99m technetium signals and ApoFlamma signals. Tumor reduction had a stronger correlation with apoptosis imaging signals than with gamma camera imaging signals, which reflect I uptake. Higher NIS-expressing tumors showed increased apoptosis and I uptake, resulting in a significant tumor reduction. Moreover, tumor reduction showed a strong correlation with ApoFlamma imaging compared to I-uptake imaging. PMID:25431214

Jung, Kyung Oh; Youn, Hyewon; Kim, Young-Hwa; Kim, Seunghoo; Na, Juri; Kim, Yong-Il; Park, Jin Woo; Kang, Keon Wook; Lee, Dong Soo; Chung, June-Key

2014-11-01

34

Gene therapy on the move  

PubMed Central

The first gene therapy clinical trials were initiated more than two decades ago. In the early days, gene therapy shared the fate of many experimental medicine approaches and was impeded by the occurrence of severe side effects in a few treated patients. The understanding of the molecular and cellular mechanisms leading to treatment- and/or vector-associated setbacks has resulted in the development of highly sophisticated gene transfer tools with improved safety and therapeutic efficacy. Employing these advanced tools, a series of Phase I/II trials were started in the past few years with excellent clinical results and no side effects reported so far. Moreover, highly efficient gene targeting strategies and site-directed gene editing technologies have been developed and applied clinically. With more than 1900 clinical trials to date, gene therapy has moved from a vision to clinical reality. This review focuses on the application of gene therapy for the correction of inherited diseases, the limitations and drawbacks encountered in some of the early clinical trials and the revival of gene therapy as a powerful treatment option for the correction of monogenic disorders. PMID:24106209

Kaufmann, Kerstin B; Büning, Hildegard; Galy, Anne; Schambach, Axel; Grez, Manuel

2013-01-01

35

ADENOVIRAL GENE THERAPY FOR OVARIAN CANCER  

E-print Network

ADENOVIRAL GENE THERAPY FOR OVARIAN CANCER Anna Kanerva Cancer Gene Therapy Group Rational Drug;SUPERVISED BY Docent Akseli Hemminki, M.D., Ph.D. Cancer Gene Therapy Group, Rational Drug Design Program ................................................................................26 9. Adenoviral gene therapy trials for ovarian cancer

Hemminki, Akseli

36

Long-term in vivo imaging of translated RNAs for gene therapy.  

PubMed

To determine the potential of RNA for transient expression, we followed its translational efficiency and expression kinetics in vivo in mouse skin. Three RNA species were delivered in vivo with differing 5' and 3' ends, as well as with different structures that are known to influence their translation fate, such as an internal ribosome entry site (IRES), a cap or a poly(A) tail. RNAs were transferred by electropermeabilization, and each encoded the firefly luciferase enzyme to allow monitoring of translational efficiency by in vivo bioluminescence imaging. We show that all types of naked RNAs delivered into mouse skin are efficient for transient protein expression in vivo. Expression could be achieved with some differences in efficiency and time course, using either capped/polyadenylated RNAs or RNAs containing HCV IRES structures with or without a poly(A) tail. Our data reveal expression occurring up to 2 weeks, suggesting that electroporated RNA has high stability in vivo, particularly capped and polyadenylated RNAs. Our study shows that RNA molecules are efficient tools for the transient expression of proteins in vivo and that they can be used for therapeutic purposes. Changes in RNA features may be used to modulate both expression efficiency and kinetics. PMID:24430234

Pinel, K; Lacoste, J; Plane, G; Ventura, M; Couillaud, F

2014-04-01

37

Gene therapy\\/cell therapy for lysosomal storage disease  

Microsoft Academic Search

Lysosomal storage diseases (LSD) are considered to be appropriate disorders for gene therapy\\/cell therapy. We are attempting to treat one of these disorders using a mouse model, the Sly mouse. This is an authentic model for human ß-glucuronidase deficiency, MPS VII. We have carried out two types of experimental protocols; in vivo gene therapy and ex vivo gene therapy using

Y. Eto; T. Ohashi

2000-01-01

38

Progress toward Human Gene Therapy  

Microsoft Academic Search

Current therapies for most human genetic diseases are inadequate. In response to the need for effective treatments, modern molecular genetics is providing tools for an unprecedented new approach to disease treatment through an attack directly on mutant genes. Recent results with several target organs and gene transfer techniques have led to broad medical and scientific acceptance of the feasibility of

Theodore Friedmann

1989-01-01

39

Coronary restenosis and gene therapy.  

PubMed Central

Restenosis continues to limit the efficacy of coronary angioplasty, despite the various mechanical and pharmaceutical interventions that have been employed. The migration, proliferation, and extracellular matrix production by vascular smooth muscle cells are processes integral to restenosis, and sustained local delivery of drugs at high concentration should curtail these vascular responses to balloon angioplasty. Our laboratory and others are exploring the potential of using somatic cell gene therapy to provide such treatment and thereby prevent restenosis. However, conventional methods of gene transfer fail to produce physiologic levels of recombinant protein in vivo. This obstacle might be overcome by using adenoviral vectors to mediate efficient direct gene transfer. Herein we summarize these developments and focus upon our laboratory's progress towards evaluating adenovirus-mediated gene therapy in porcine coronary arteries. Recombinant adenoviruses directing the expression of the beta-galactosidase and luciferase reporter genes were evaluated in cultured coronary vascular smooth muscle cells in vitro and in porcine coronary arteries in vivo. Following percutaneous transluminal gene transfer in vivo, recombinant adenoviruses were shown to produce 70- to 240-fold more reporter protein than that produced by Lipofectin-DNA complexes. Furthermore, the high levels of adenovirus-mediated gene expression were shown to persist for at least 14 days following catheterization. Additional histologic studies will be required to determine the cellular distribution of gene expression and to elucidate potential interactions between adenovirus and the host's immune system, but recombinant adenovirus appears to be a promising vector for evaluating gene therapy against coronary restenosis. PMID:8180504

Mazur, W; Ali, N M; Raizner, A E; French, B A

1994-01-01

40

Gene Therapy in Corneal Transplantation  

PubMed Central

Corneal transplantation is the most commonly performed organ transplantation. Immune privilege of the cornea is widely recognized, partly because of the relatively favorable outcome of corneal grafts. The first-time recipient of corneal allografts in an avascular, low-risk setting can expect a 90% success rate without systemic immunosuppressive agents and histocompatibility matching. However, immunologic rejection remains the major cause of graft failure, particularly in patients with a high risk for rejection. Corticosteroids remain the first-line therapy for the prevention and treatment of immune rejection. However, current pharmacological measures are limited in their side-effect profiles, repeated application, lack of targeted response, and short duration of action. Experimental ocular gene therapy may thus present new horizons in immunomodulation. From efficient viral vectors to sustainable alternative splicing, we discuss the progress of gene therapy in promoting graft survival and postulate further avenues for gene-mediated prevention of allogeneic graft rejection. PMID:24138037

Qazi, Yureeda; Hamrah, Pedram

2014-01-01

41

Gene therapy in clinical medicine  

PubMed Central

Although the field of gene therapy has experienced significant setbacks and limited success, it is one of the most promising and active research fields in medicine. Interest in this therapeutic modality is based on the potential for treatment and cure of some of the most malignant and devastating diseases affecting humans. Over the next decade, the relevance of gene therapy to medical practices will increase and it will become important for physicians to understand the basic principles and strategies that underlie the therapeutic intervention. This report reviews the history, basic strategies, tools, and several current clinical paradigms for application. PMID:15466989

Selkirk, S

2004-01-01

42

Ethics of Gene Therapy Debated.  

ERIC Educational Resources Information Center

Presented are the highlights of a press conference featuring biomedical ethicist LeRoy Walters of Georgetown University and attorney Andrew Kimbrell of the Foundation on Economic Trends. The opposing points of view of these two speakers serve to outline the pros and cons of the gene therapy issue. (CW)

Borman, Stu

1991-01-01

43

Gene therapy for lung cancer.  

PubMed

Lung cancer patients suffer a 15% overall survival despite advances in chemotherapy, radiation therapy, and surgery. This unacceptably low survival rate is due to the usual finding of advanced disease at diagnosis. However, multimodality strategies using conventional therapies only minimally improve survival rates even in early stages of lung cancer. Attempts to improve survival in advanced disease using various combinations of platinum-based chemotherapy have demonstrated that no regimen is superior, suggesting a therapeutic plateau and the need for novel, more specific, and less toxic therapeutic strategies. Over the past three decades, the genetic etiology of cancer has been gradually delineated, albeit not yet completely. Understanding the molecular events that occur during the multistep process of bronchogenic carcinogenesis may make these tasks more surmountable. During these same three decades, techniques have been developed which allow transfer of functional genes into mammalian cells. For example, blockade of activated tumor-promoting oncogenes or replacement of inactivated tumor-suppressing or apoptosis-promoting genes can be achieved by gene therapy. This article will discuss the therapeutic implications of these molecular changes associated with bronchogenic carcinomas and will then review the status of gene therapies for treatment of lung cancer. PMID:16767697

Toloza, Eric M; Morse, Michael A; Lyerly, H Kim

2006-09-01

44

Orthopedic Gene Therapy in 2008  

Microsoft Academic Search

Orthopedic disorders, although rarely fatal, are the leading cause of morbidity and impose a huge socioeconomic burden. Their prevalence will increase dramatically as populations age and gain weight. Many orthopedic conditions are difficult to treat by conventional means; however, they are good candidates for gene therapy. Clinical trials have already been initiated for arthritis and the aseptic loosening of prosthetic

Christopher H Evans; Steven C Ghivizzani; Paul D Robbins

2009-01-01

45

American Society of Gene & Cell Therapy  

MedlinePLUS

... Professor University of Iowa The American Society of Gene & Cell Therapy ASGCT's MISSION is to advance knowledge, ... Therapeutics Official Journal of the American Society of Gene & Cell Therapy 2013 Impact Factor: 6.425 Current ...

46

Gene Therapy for Bone Engineering  

PubMed Central

Bone has an intrinsic healing capacity that may be exceeded when the fracture gap is too big or unstable. In that moment, osteogenic measures need to be taken by physicians. It is important to combine cells, scaffolds and growth factors, and the correct mechanical conditions. Growth factors are clinically administered as recombinant proteins. They are, however, expensive and needed in high supraphysiological doses. Moreover, their half-life is short when administered to the fracture. Therefore, gene therapy may be an alternative. Cells can constantly produce the protein of interest in the correct folding, with the physiological glycosylation and in the needed amounts. Genes can be delivered in vivo or ex vivo by viral or non-viral methods. Adenovirus is mostly used. For the non-viral methods, hydrogels and recently sonoporation seem to be promising means. This review will give an overview of recent advancements in gene therapy approaches for bone regeneration strategies.

Balmayor, Elizabeth Rosado; van Griensven, Martijn

2015-01-01

47

Gene therapy for lung cancer.  

PubMed

Lung cancer patients suffer a 15% overall survival despite advances in chemotherapy, radiation therapy, and surgery due to the usual finding of advanced disease at diagnosis. Attempts to improve survival in advanced disease using various combinations of chemotherapy have demonstrated that no regimen is superior, suggesting a therapeutic plateau and the need for novel, more specific, and less toxic therapeutic strategies. Techniques have been developed that allow transfer of functional genes into mammalian cells, such as those that block activated tumor-promoting oncogenes and/or those that replace inactivated tumor-suppressing or apoptosis-promoting genes. This article will discuss the therapeutic implications of these molecular changes associated with bronchogenic carcinomas, and will then review the status of gene therapies for treatment of lung cancer. PMID:17240826

Toloza, Eric M

2006-11-01

48

Combination of Gene Therapy with Radiation  

Microsoft Academic Search

To date tremendous progress has been made in the field of cancer gene therapy. Strategies have been explored for achieving\\u000a therapeutic benefit using various genes and several clinical trials for cancer gene therapy have been carried out demonstrating\\u000a that gene therapy is well tolerated. However, in most cases the efficacy of gene transfer has been very limited. As an alternative,

Anupama Munshi; Raymond E. Meyn

49

Gene therapy for ovarian cancer  

Microsoft Academic Search

Ovarian cancer remains the leading cause of death due to gynecologic cancer in women in the United States. Gene and viral-based\\u000a therapies represent novel therapeutic approaches for cancer. The manipulation of genetic content of tumor cells toward a therapeutic\\u000a end has been divided into several general strategies, including molecular chemotherapy, mutation compensation, immunopotentiation,\\u000a and virotherapy. Improvements in delivery vehicles and

Kristopher J. Kimball; T. Michael Numnum; Rodney P. Rocconi; Ronald D. Alvarez

2006-01-01

50

Orthopedic Gene Therapy in 2008  

PubMed Central

Orthopedic disorders, although rarely fatal, are the leading cause of morbidity and impose a huge socioeconomic burden. Their prevalence will increase dramatically as populations age and gain weight. Many orthopedic conditions are difficult to treat by conventional means; however, they are good candidates for gene therapy. Clinical trials have already been initiated for arthritis and the aseptic loosening of prosthetic joints, and the development of bone-healing applications is at an advanced, preclinical stage. Other potential uses include the treatment of Mendelian diseases and orthopedic tumors, as well as the repair and regeneration of cartilage, ligaments, and tendons. Many of these goals should be achievable with existing technologies. The main barriers to clinical application are funding and regulatory issues, which in turn reflect major safety concerns and the opinion, in some quarters, that gene therapy should not be applied to nonlethal, nongenetic diseases. For some indications, advances in nongenetic treatments have also diminished enthusiasm. Nevertheless, the preclinical and early clinical data are impressive and provide considerable optimism that gene therapy will provide straightforward, effective solutions to the clinical management of several common debilitating disorders that are otherwise difficult and expensive to treat. PMID:19066598

Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D

2008-01-01

51

Advancement and prospects of tumor gene therapy  

PubMed Central

Gene therapy is one of the most attractive fields in tumor therapy. In past decades, significant progress has been achieved. Various approaches, such as viral and non-viral vectors and physical methods, have been developed to make gene delivery safer and more efficient. Several therapeutic strategies have evolved, including gene-based (tumor suppressor genes, suicide genes, antiangiogenic genes, cytokine and oxidative stress-based genes) and RNA-based (antisense oligonucleotides and RNA interference) approaches. In addition, immune response-based strategies (dendritic cell– and T cell–based therapy) are also under investigation in tumor gene therapy. This review highlights the progress and recent developments in gene delivery systems, therapeutic strategies, and possible clinical directions for gene therapy. PMID:21352695

Zhang, Chao; Wang, Qing-Tao; Liu, He; Zhang, Zhen-Zhu; Huang, Wen-Lin

2011-01-01

52

Gene therapy using retroviral vectors.  

PubMed

Gene therapy is a novel approach for treating various congenital and acquired genetic disorders, including cancer, heart disease, and acquired immune deficiency syndrome. Amongst possible gene delivery systems, retroviral vector mediated gene transfer has been the most extensively studied and has been approved for use in over 40 current Phase I/II clinical trials for the treatment of various disorders, primarily cancers. Recent technological improvements include the optimization of vector production by concentration and lyophilization, resulting in high titers of vectors, as well as the large-scale production of vector-produced cells for the treatment of brain cancer. Present clinical protocols require specialized care centers with expertise in molecular biology and cell transplantation. Considerable effort is under way to develop retroviral vectors that can be both injected directly into the body and targeted to specific cell types within the body. Such vectors could be administered to patients by physicians in their offices. Successful development of this new technology would greatly expand the clinical potential of gene therapy. PMID:7765744

Gordon, E M; Anderson, W F

1994-12-01

53

GENE THERAPY IN ORAL CANCER: AN OVERVIEW  

E-print Network

The treatment and prevention of oral cancer is one of the major hurdles in the field of cancer. Gene therapy is one of the recent advances in this field to tackle this hurdle with promising prospects. This overview introduces the reader into the basic idea of gene therapy, types of gene therapy and the various modes of introduction of therapeutic gene into the cancer affected cell.

unknown authors

54

Cancer Treatment with Gene Therapy and Radiation Therapy  

PubMed Central

Radiation therapy methods have evolved remarkably in recent years which have resulted in more effective local tumor control with negligible toxicity of surrounding normal tissues. However, local recurrence and distant metastasis often occur following radiation therapy mostly due to the development of radioresistance through the deregulation of the cell cycle, apoptosis, and inhibition of DNA damage repair mechanisms. Over the last decade, extensive progress in radiotherapy and gene therapy combinatorial approaches has been achieved to overcome resistance of tumor cells to radiation. In this review, we summarize the results from experimental cancer therapy studies on the combination of radiation therapy and gene therapy. PMID:23021246

Kaliberov, Sergey A.; Buchsbaum, Donald J.

2013-01-01

55

Gene therapy for sensorineural hearing loss.  

PubMed

Gene therapy is a promising treatment modality that is being explored for several inherited disorders. Multiple human gene therapy clinical trials are currently ongoing, but few are directed at hearing loss. Hearing loss is one of the most prevalent sensory disabilities in the world, and genetics play an important role in the pathophysiology of hearing loss. Gene therapy offers the possibility of restoring hearing by overcoming the functional deficits created by the underlying genetic mutations. In addition, gene therapy could potentially be used to induce hair cell regeneration by delivering genes that are critical to hair cell differentiation into the cochlea. In this review, we examine the promises and challenges of applying gene therapy to the cochlea. We also summarize recent studies that have applied gene therapy to animal models of hearing loss. PMID:25166629

Chien, Wade W; Monzack, Elyssa L; McDougald, Devin S; Cunningham, Lisa L

2015-01-01

56

Gene technology: chances for diagnosis and therapy.  

PubMed

In the case of a single gene defect, a number of appropriate gene probes are available for prenatal diagnosis. In some cases, knowledge of the genetic disorders enables early onset of therapy or the option for abortion. However, gene technology which enables the diagnosis should not be viewed from an ethical point of view but rather the action taken when diagnostic results are available. Gene therapy for a single gene defect still is at the early stage of development. Only a few patients have been treated in various indications. Difficult to overcome are the low frequency and unspecific integration of inserted DNA into the chromosome, lack of sufficient transcription control, and short half-life of the integrated gene. From an ethical perspective gene therapy complies with the therapeutic concept of medicine. Antisense oligonucleotides are under clinical development for blockage of the synthesis of oncogenes and viral proteins. Stability of oligonucleotides as well as selectivity for specific cells will have to be overcome for broader application. Its therapeutic application is in accordance with the ethical principles of medicine. Substitution therapies with recombinant DNA derived human proteins are in therapeutic application to replace their counterparts from native source in a safer way or for human pharmacologically active proteins which cannot be isolated from their natural source. For recombinant DNA derived proteins where the mode of action is known, short development time frames can be expected allowing for an early return on investment. The expected market potential for recombinant DNA derived pharmaceuticals in 1995 will reach 4,400 million DM. Due to their specificity, monoclonal antibodies are used for tumor imaging when labeled by 99mtechnetium or for tumor therapy when labeled by rhenium or yttrium. Both concepts are under clinical evaluation. Vaccines derived from recombinant DNA technology offer the chance of producing safer vaccines consisting of the antigen determinant only. In general, recombinant DNA technology and biotechnology offer the opportunity of providing new diagnostic and therapeutic principles of high ethical value. The biotechnical manufacturing processes used for this purpose are friendly to the environment by using raw material from renewable sources, low energy consumption, and producing biodegradable products only. In almost all cases, host cells used for manufacturing belong to the safety category 1, in which no danger is expected for the operator, the public, and the environment.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7885080

Werner, R G

1994-09-01

57

Gene therapy for the hemophilias.  

PubMed

There are many lines of evidence that suggest the eventual success of gene therapy as a treatment strategy for hemophilia. Because current treatment protocols using plasma-derived or recombinant proteins are far from ideal, the safe and efficient substitution of the defective gene by a normal copy of the gene, or at least its addition, would be of great benefit to the patient and may even be a potential cure. However, the construction of efficient gene therapy vehicles has proven quite difficult in the past and, so far, there is no system that promises to have all the desired features without any serious disadvantages. In general, either the levels of transgene expression are too low (because of the low titers achieved during the generation of the virus) or shortlived (e.g., because of the specific shut-off of the transferred promoter) as is often seen with retroviruses, or in the case of adenoviral vectors, expression is limited because of a strong immune response of the host. Clearly, much work remains to be done to optimize these promising though still imperfect vector systems. In the case of adenovirus, the development of less immunogenic vectors or in vivo modulation of the host immune system may hold promise for improvements. Reports by Yang et al. (1995) and Kay et al. (1995) are promising steps in the direction of immunomodulation. Both attenuate the immune reaction to the adenoviral vector by simultaneous application of either an interleukin or an immunoglobulin, respectively. When IL-2 was administered, the amounts of IgA were reduced and successful administration of a second dose of virus was possible. When CTLA4-Ig, an immunoglobulin that blocks the second signal during antigen presentation, was administered, a markedly prolonged expression of the transgene resulted. In vivo trials with AAV vectors have been carried out for some diseases (Flotte et al., 1993; Kaplitt et al., 1994) but not for hemophilia. Advances in high-titer AAV vector preparation will make this approach more feasible. The pace continues to quicken in the development of nonviral modes of gene delivery (Perales et al., 1994). Although these results are encouraging for the future of gene therapy as a treatment for genetic diseases, much work remains to be done to make this potential alternative a reality for treatment of hemophilia. PMID:9395731

Walter, J; High, K A

1997-01-01

58

Regulatory issues in human gene therapy.  

PubMed

Protection of human subjects is the ethical and legal responsibility of investigators conducting clinical trials. Public concerns regarding recombinant DNA technology led to additional levels of oversight which are unique to human gene therapy trials. The deaths of a normal volunteer and a gene therapy subject in the late 1990s led to an intensification of oversight with new initiatives that impact gene therapy as well as other clinical investigators. This paper will review the current oversight agencies and identify areas of evolving regulations that pose particular challenges to gene therapy investigators. PMID:12850484

Cornetta, Kenneth

2003-01-01

59

Molecular Imaging and Targeted Therapies  

PubMed Central

Targeted therapeutic and imaging agents are becoming more prevalent, and are used to treat increasingly smaller segments of the patient population. This has lead to dramatic increases in the costs for clinical trials. Biomarkers have great potential to reduce the numbers of patients needed to test novel targeted agents by predicting or identifying non-response early-on and thus enriching the clinical trial population with patients more likely to respond. Biomarkers are characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers can be used to predict response to specific therapies, predict response regardless of therapy, or to monitor response once a therapy has begun. In terms of drug development, predictive biomarkers have the greatest impact, as they can be used as inclusion criteria for patient segmentation. Prognostic markers are used routinely in clinical practice but do not provide direction for the use of targeted therapies. Imaging biomarkers have distinct advantages over those that require a biopsy sample in that they are “non-invasive” and can be monitored longitudinally at multiple time points in the same patient. This review will examine the role of functional and molecular imaging in predicting response to specific therapies; will explore the advantages and disadvantages of targeting intracellular or extracellular markers; and will discuss the attributes of useful targets and methods for target identification and validation. PMID:20399197

Morse, David L.; Gillies, Robert J.

2010-01-01

60

Gene Therapy Progress and Prospects: Nonviral vectors  

Microsoft Academic Search

The success of gene therapy is largely dependent on the development of the gene delivery vector. Recently, gene transfection into target cells using naked DNA, which is a simple and safe approach, has been improved by combining several physical techniques, for example, electroporation, gene gun, ultrasound and hydrodynamic pressure. Chemical approaches have been utilized to improve the efficiency and cell

T Niidome; L Huang

2002-01-01

61

Regulatory issues for clinical gene therapy trials.  

PubMed

Gene therapy trials are among the most heavily regulated clinical trials. In this review, the basic tenets of human subject research are discussed in the context of the regulatory bodies which oversee this work. The challenges faced by academic research are outlined, including new and proposed regulations which impact human gene therapy investigators. PMID:12133267

Cornetta, Kenneth; Smith, Franklin O

2002-07-01

62

New perspectives for gene therapy in endocrinology  

Microsoft Academic Search

Gene therapy for endocrine diseases represents an exciting new type of molecular intervention that may be a curative one. Endocrine disorders that might be treated by gene therapy include monogenic diseases, such as GH deficiency and hypothalamic diabetes insipidus, and multifactorial diseases, such as diabetes mellitus, obesity and cancer. Premises seem promising for endocrine tumours, but many combined approaches of

Luisa Barzon; Roberta Bonaguro; Giorgio Palu; Marco Boscaro

2000-01-01

63

Gene therapy prospects--intranasal delivery of therapeutic genes.  

PubMed

Gene therapy is recognized to be a novel method for the treatment of various disorders. Gene therapy strategies involve gene manipulation on broad biological processes responsible for the spreading of diseases. Cancer, monogenic diseases, vascular and infectious diseases are the main targets of gene therapy. In order to obtain valuable experimental and clinical results, sufficient gene transfer methods are required. Therapeutic genes can be administered into target tissues via gene carriers commonly defined as vectors. The retroviral, adenoviral and adeno-associated virus based vectors are most frequently used in the clinic. So far, gene preparations may be administered directly into target organs or by intravenous, intramuscular, intratumor or intranasal injections. It is common knowledge that the number of gene therapy clinical trials has rapidly increased. However, some limitations such as transfection efficiency and stable and long-term gene expression are still not resolved. Consequently, great effort is focused on the evaluation of new strategies of gene delivery. There are many expectations associated with intranasal delivery of gene preparations for the treatment of diseases. Intranasal delivery of therapeutic genes is regarded as one of the most promising forms of pulmonary gene therapy research. Gene therapy based on inhalation of gene preparations offers an alternative way for the treatment of patients suffering from such lung diseases as cystic fibrosis, alpha-1-antitrypsin defect, or cancer. Experimental and first clinical trials based on plasmid vectors or recombinant viruses have revealed that gene preparations can effectively deliver therapeutic or marker genes to the cells of the respiratory tract. The noninvasive intranasal delivery of gene preparations or conventional drugs seems to be very encouraging, although basic scientific research still has to continue. PMID:23240459

Podolska, Karolina; Stachurska, Anna; Hajdukiewicz, Karolina; Ma?ecki, Maciej

2012-01-01

64

Adenoviral Vectors for Hemophilia Gene Therapy  

PubMed Central

Hemophilia is an inherited blood clotting disorder resulting from deficiency of blood coagulation factors. Current standard of care for hemophilia patients is frequent intravenous infusions of the missing coagulation factor. Gene therapy for hemophilia involves the introduction of a normal copy of the deficient coagulation factor gene thereby potentially offering a definitive cure for the bleeding disorder. A variety of approaches have been pursued for hemophilia gene therapy and this review article focuses on those that use adenoviral vectors. PMID:24883229

Brunetti-Pierri, N; Ng, Philip

2013-01-01

65

Adenoviral Vectors for Hemophilia Gene Therapy.  

PubMed

Hemophilia is an inherited blood clotting disorder resulting from deficiency of blood coagulation factors. Current standard of care for hemophilia patients is frequent intravenous infusions of the missing coagulation factor. Gene therapy for hemophilia involves the introduction of a normal copy of the deficient coagulation factor gene thereby potentially offering a definitive cure for the bleeding disorder. A variety of approaches have been pursued for hemophilia gene therapy and this review article focuses on those that use adenoviral vectors. PMID:24883229

Brunetti-Pierri, N; Ng, Philip

2013-04-30

66

PET imaging of adoptive progenitor cell therapies.  

SciTech Connect

Objectives. The overall objective of this application is to develop novel technologies for non-invasive imaging of adoptive stem cell-based therapies with positron emission tomography (PET) that would be applicable to human patients. To achieve this objective, stem cells will be genetically labeled with a PET-reporter gene and repetitively imaged to assess their distribution, migration, differentiation, and persistence using a radiolabeled reporter probe. This new imaging technology will be tested in adoptive progenitor cell-based therapy models in animals, including: delivery pro-apoptotic genes to tumors, and T-cell reconstitution for immunostimulatory therapy during allogeneic bone marrow progenitor cell transplantation. Technical and Scientific Merits. Non-invasive whole body imaging would significantly aid in the development and clinical implementation of various adoptive progenitor cell-based therapies by providing the means for non-invasive monitoring of the fate of injected progenitor cells over a long period of observation. The proposed imaging approaches could help to address several questions related to stem cell migration and homing, their long-term viability, and their subsequent differentiation. The ability to image these processes non-invasively in 3D and repetitively over a long period of time is very important and will help the development and clinical application of various strategies to control and direct stem cell migration and differentiation. Approach to accomplish the work. Stem cells will be genetically with a reporter gene which will allow for repetitive non-invasive “tracking” of the migration and localization of genetically labeled stem cells and their progeny. This is a radically new approach that is being developed for future human applications and should allow for a long term (many years) repetitive imaging of the fate of tissues that develop from the transplanted stem cells. Why the approach is appropriate. The novel approach to stem cell imaging is proposed to circumvent the major limitation of in vitro radiolabeling – the eventual radiolabel decay. Stable transduction of stem cells in vitro would allow for the selection of high quality stem cells with optimal functional parameters of the transduced reporter systems. The use of a long-lived radioisotope 124I to label a highly specific reporter gene probe will allow for ex vivo labeling of stem cells and their imaging immediately after injection and during the following next week. The use of short-lived radioisotopes (i.e., 18F) to label highly specific reporter gene probes will allow repetitive PET imaging for the assessment of to stem cell migration, targeting, differentiation, and long-term viability of stem cell-derived tissues. Qualifications of the research team and resources. An established research team of experts in various disciplines has been assembled at MD Anderson Cancer Center (MDACC) over the past two years including the PI, senior co-investigators and collaborators. The participants of this team are recognized internationally to be among the leaders in their corresponding fields of research and clinical medicine. The resources at MDACC are exceptionally well developed and have been recently reinforced by the installation of a microPET and microSPECT/CT cameras, and a 7T MRI system for high resolution animal imaging; and by integrating a synthetic chemistry core for the development and production of precursors for radiolabeling.

Gelovani, Juri G.

2008-05-13

67

Cancer gene therapy--fantasy or foresight?  

PubMed

Gene therapy is an exciting new method of treatment that may have far-reaching implications on the way we manage diseases in the future. Cancer has become the principal focus of this futuristic research. The breathtaking pace of gene discovery in the last two decades, coupled with the birth of recombinant DNA technology, gave rise to the concept that genes may be manipulated and used as drugs. Genetic modification of cells can be carried out in petri dishes (ex vivo) or within the living system (in vivo). In order for the therapeutic genes to exert their effect, they have to be transported into the cell nucleus where transcription takes place. Liposomes and genetically modified viruses have been extensively used as gene vectors. The ideal vector remains elusive. It would be one that can achieve tumour-specific, sustained, and regulatable gene expression without host toxicity. As a result of the past decade of intense gene therapy research, we have learned that it is a rational scientific concept that works remarkably well in petri dishes and in laboratory animals. However, early clinical gene therapy experimentations paled in comparison. This apparent disparity between dramatic preclinical successes and the very modest clinical results of gene therapy does not in anyway nullify the concept of gene therapy. Instead, it exposes the folly of underestimating the technical complexity of gene manipulation in human diseases. Fortunately, technical hurdles such as those confronting gene therapy today are not insurmountable; they need, however, much ingenuity, resolution and time to be overcome. It is reassuring that recent advances in gene therapy provide abundant evidence that the premature infant, born of unrealistic pressure, is indeed healthy and thriving. With proper nurturing and patience, there is no doubt that, in time, it will bear fruit. PMID:10575528

Kong, H L

1999-05-01

68

Improving enzymes for cancer gene therapy  

Microsoft Academic Search

New techniques now make it feasible to tailor enzymes for cancer gene therapy. Novel enzymes with desired properties can be created and selected from vast libraries of mutants containing random substitutions within catalytic domains. In this review, we first consider genes for the ablation of tumors, namely, genes that have been mutated (or potentially can be mutated) to afford enhanced

Lance P. Encell; Daniel M. Landis; Lawrence A. Loeb

1999-01-01

69

Phenotyping Cardiac Gene Therapy in Mice  

PubMed Central

Heart disease is the leading health problem of industrialized countries. The development of gene therapies tailored towards the heart has grown exponentially over the past decade. Murine models of heart diseases have played a pivotal role in testing novel cardiac gene therapy approaches. Unfortunately, the small body size and rapid heart rate of mice present a great challenge to heart function evaluation. Here we outline the commonly used cardiac phenotyping methods of treadmill exercise regimen, full 12-lead electrocardiographic assay and left ventricular catheterization hemodynamic assay. Application of these protocols will allow critical testing of gene therapy efficacy in mouse models of heart diseases. PMID:21194023

Bostick, Brian; Yue, Yongping; Duan, Dongsheng

2011-01-01

70

Gene Therapy Techniques for Peripheral Arterial Disease  

SciTech Connect

Somatic gene therapy is the introduction of new genetic material into selective somatic cells with resulting therapeutic benefits. Vascular wall and, subsequently, cardiovascular diseases have become an interesting target for gene therapy studies.Arteries are an attractive target for gene therapy since vascular interventions, both open surgical and endovascular, are well suited for minimally invasive, easily monitored gene delivery. Promising therapeutic effects have been obtained in animal models in preventing post-angioplasty restenosis and vein graft thickening, as well as increasing blood flow and collateral development in ischemic limbs.First clinical trials suggest a beneficial effect of vascular endothelial growth factor in achieving therapeutic angiogenesis in chronic limb ischemia and the efficacy of decoy oligonucleotides to prevent infrainguinal vein graft stenosis. However, further studies are mandatory to clarify the safety issues, to develop better gene delivery vectors and delivery catheters, to improve transgene expression, as well as to find the most effective and safe treatment genes.

Manninen, Hannu I. [Department of Clinical Radiology, Kuopio University Hospital, Puijonlaaksontie 2, FIN-70210 Kuopio (Finland); Maekinen, Kimmo [Departmentof Surgery, and Gene Therapy Unit, Kuopio University Hospital, Puijonlaaksontie 2, FIN-70210 Kuopio (Finland)

2002-03-15

71

MOLECULAR THERAPY Vol. 4, No. 2, August 2001 Copyright The American Society of Gene Therapy  

E-print Network

MOLECULAR THERAPY Vol. 4, No. 2, August 2001 Copyright © The American Society of Gene Therapy 1525 expression may be an effective gene therapy vector design, if the target cells are dividing. The efficacy that are therapeutically relevant for gene therapy. Key words: 1-antitrypsin, Epstein-Barr virus, gene therapy, genomic DNA

Ford, James

72

Cancer-Related Gene Therapy Clinical Trials  

Microsoft Academic Search

Gene therapy represents a strategy using transfer of genetic information to modify a population of target cells for therapeutic\\u000a purposes. The transferred genetic material has typically included double-stranded deoxyribonucleic acid (DNA), but occasionally\\u000a single-stranded DNA and even ribonucleic acid (RNA). Gene therapy represents one of the many novel “targeted” antineoplastic\\u000a treatment approaches with the goal to inhibit the growth of

Robert J. Korst; Ronald G. Crystal

73

LSUHSC Gene Therapy Program External Grant Awards  

E-print Network

generated dendritic cells · Adult stem cell mediated gene therapy for cystic fibrosis STATE AWARDS: $15- Based Therapy for Cystic Fibrosis · Immunotherapy of Bacterial pneumonia in HIV infections · Center and in-vitro fertilized domstic cat embryos · Bacterial killing of Neutrophils for Cystic Fibrosis

74

Cardiovascular gene therapy for myocardial infarction  

PubMed Central

Introduction Cardiovascular gene therapy is the third most popular application for gene therapy, representing 8.4% of all gene therapy trials as reported in 2012 estimates. Gene therapy in cardiovascular disease is aiming to treat heart failure from ischemic and non-ischemic causes, peripheral artery disease, venous ulcer, pulmonary hypertension, atherosclerosis and monogenic diseases, such as Fabry disease. Areas covered In this review, we will focus on elucidating current molecular targets for the treatment of ventricular dysfunction following myocardial infarction (MI). In particular, we will focus on the treatment of i) the clinical consequences of it, such as heart failure and residual myocardial ischemia and ii) etiological causes of MI (coronary vessels atherosclerosis, bypass venous graft disease, in-stent restenosis). Expert opinion We summarise the scheme of the review and the molecular targets either already at the gene therapy clinical trial phase or in the pipeline. These targets will be discussed below. Following this, we will focus on what we believe are the 4 prerequisites of success of any gene target therapy: safety, expression, specificity and efficacy (SESE). PMID:24328708

Scimia, Maria C; Gumpert, Anna M; Koch, Walter J

2014-01-01

75

Strategies in Gene Therapy for Glioblastoma  

PubMed Central

Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy. PMID:24202446

Kwiatkowska, Aneta; Nandhu, Mohan S.; Behera, Prajna; Chiocca, E. Antonio; Viapiano, Mariano S.

2013-01-01

76

Progress in gene therapy for neurological disorders  

PubMed Central

Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy. PMID:23609618

Simonato, Michele; Bennett, Jean; Boulis, Nicholas M.; Castro, Maria G.; Fink, David J.; Goins, William F.; Gray, Steven J.; Lowenstein, Pedro R.; Vandenberghe, Luk H.; Wilson, Thomas J.; Wolfe, John H.; Glorioso, Joseph C.

2013-01-01

77

Sodium-iodine Symporter Gene Expression Controlled by the EGR-1 Promoter: Biodistribution, Imaging and in vitro Radionuclide Therapy with Na131I.  

PubMed

The objective of this study is to explore the feasibility of radioiodine treatment for cervical cancer using the early growth response (Egr-1) promoter to control sodium-iodine symporter (hNIS) gene expression. The hNIS gene was previously transfected into Hela cells under the control of either the cytomegalovirus (CMV) or Egr-1 promoters. Na(125)I uptake was measured in the presence or absence of NaClO4. Na(125)I efflux was measured. The effects of external beam radiation on iodine uptake and retention were studied. The cytotoxic effects of (131)I were measured by clonogenic assay. The Na(125)I biodistribution was obtained using mice bearing control and transfected cells. The %ID/g of tumor and major organs were obtained for a range of times up to 48 hours post injection and the ratio of tumor to non-tumor activity (T/NT) was calculated. Tumors were imaged with Na(131)I and (99m)TcO4 (-), and the ratio of tumor to background activity (T/B) was calculated. Na(125)I uptake in Hela cells was minimal in the absence of hNIS. Uptake in the transfected cells was strong, and could be blocked by NaClO4. The iodine uptake of Hela-Egr-1-hNIS cells increased after the irradiation, and the magnitude of this effect approximately matched the radiation dose delivered. The efflux of 125I was affected by neither the promoter sequence nor pre-irradiation. (131)I reduced the clonogenic survival of symporter expressing cells, relative to the parental line. The effect was greatest in cells where hNIS was driven by the CMV promoter. Tumors formed from Hela-Egr-1-hNIS concentrated Na(125)I over a 12 hour period, in contrast to untransfected cells. These tumors could also be successfully imaged using either Na(131)I or (99m)TcO4 (-). (131)I uptake peaked at 4h, while (99m)TcO4 (-) accumulated over approximately 20 hours. In vivo uptake of (131)I and (99m)TcO4 (-) was slightly higher in cells transfected with the Egr-1 promoter, compared to CMV. Hela-Egr-1-hNIS cells demonstrate highly enhanced iodine uptake, and this effect is further augmented by radiation, creating a positive feedback loop which may bolster radionuclide therapy in vivo. PMID:24354753

Tang, Jun; Wang, Xiaoxia; Xu, Yuanqi; Shi, Yizhen; Liu, Zengli; Yang, Yi

2015-02-01

78

FUNCTIONAL NANOPARTICLES FOR MOLECULAR IMAGING GUIDED GENE DELIVERY  

PubMed Central

Gene therapy has great potential to bring tremendous changes in treatment of various diseases and disorders. However, one of the impediments to successful gene therapy is the inefficient delivery of genes to target tissues and the inability to monitor delivery of genes and therapeutic responses at the targeted site. The emergence of molecular imaging strategies has been pivotal in optimizing gene therapy; since it can allow us to evaluate the effectiveness of gene delivery noninvasively and spatiotemporally. Due to the unique physiochemical properties of nanomaterials, numerous functional nanoparticles show promise in accomplishing gene delivery with the necessary feature of visualizing the delivery. In this review, recent developments of nanoparticles for molecular imaging guided gene delivery are summarized. PMID:22473061

Liu, Gang; Swierczewska, Magdalena; Lee, Seulki; Chen, Xiaoyuan

2010-01-01

79

Why commercialization of gene therapy stalled; examining the life cycles of gene therapy technologies.  

PubMed

This report examines the commercialization of gene therapy in the context of innovation theories that posit a relationship between the maturation of a technology through its life cycle and prospects for successful product development. We show that the field of gene therapy has matured steadily since the 1980s, with the congruent accumulation of >35?000 papers, >16?000 US patents, >1800 clinical trials and >$4.3 billion in capital investment in gene therapy companies. Gene therapy technologies comprise a series of dissimilar approaches for gene delivery, each of which has introduced a distinct product architecture. Using bibliometric methods, we quantify the maturation of each technology through a characteristic life cycle S-curve, from a Nascent stage, through a Growing stage of exponential advance, toward an Established stage and projected limit. Capital investment in gene therapy is shown to have occurred predominantly in Nascent stage technologies and to be negatively correlated with maturity. Gene therapy technologies are now achieving the level of maturity that innovation research and biotechnology experience suggest may be requisite for efficient product development. Asynchrony between the maturation of gene therapy technologies and capital investment in development-focused business models may have stalled the commercialization of gene therapy. PMID:24305420

Ledley, F D; McNamee, L M; Uzdil, V; Morgan, I W

2014-02-01

80

Gene therapy: where to draw the line.  

PubMed

The four classifications of genetic manipulation (somatic cell gene therapy, germ-line gene therapy, enhancement genetic engineering, eugenic genetic engineering) are reviewed from an ethical viewpoint. Immediately, it needs to be recognized that words like "therapy," "enhancement," and "eugenic" already possess an emotional framework, so that careful reasoning is made more difficult. In each of the areas of genetic manipulation, it can be argued that circumstances could be imagined that would either justify or not justify proceeding. Based on our present state of knowledge, the line should be drawn at not carrying out gene therapy of any type except in specific cases that are carefully evaluated in advance. With increased knowledge, the line should be moved to embrace appropriate situations. PMID:2081196

Hoose, B

1990-01-01

81

A Comprehensive Review of Retinal Gene Therapy  

PubMed Central

Blindness, although not life threatening, is a debilitating disorder for which few, if any treatments exist. Ocular gene therapies have the potential to profoundly improve the quality of life in patients with inherited retinal disease. As such, tremendous focus has been given to develop such therapies. Several factors make the eye an ideal organ for gene-replacement therapy including its accessibility, immune privilege, small size, compartmentalization, and the existence of a contralateral control. This review will provide a comprehensive summary of (i) existing gene therapy clinical trials for several genetic forms of blindness and (ii) preclinical efficacy and safety studies in a variety of animal models of retinal disease which demonstrate strong potential for clinical application. To be as comprehensive as possible, we include additional proof of concept studies using gene replacement, neurotrophic/neuroprotective, optogenetic, antiangiogenic, or antioxidative stress strategies as well as a description of the current challenges and future directions in the ocular gene therapy field to this review as a supplement. PMID:23358189

Boye, Shannon E; Boye, Sanford L; Lewin, Alfred S; Hauswirth, William W

2013-01-01

82

Image-Guided Tumor-Selective Radioiodine Therapy of Liver Cancer After Systemic Nonviral Delivery of the Sodium Iodide Symporter Gene  

PubMed Central

Abstract We reported the induction of tumor-selective iodide uptake and therapeutic efficacy of 131I in a hepatocellular carcinoma (HCC) xenograft mouse model, using novel polyplexes based on linear polyethylenimine (LPEI), shielded by polyethylene glycol (PEG), and coupled with the epidermal growth factor receptor-specific peptide GE11 (LPEI-PEG-GE11). The aim of the current study in the same HCC model was to evaluate the potential of biodegradable nanoparticle vectors based on pseudodendritic oligoamines (G2-HD-OEI) for systemic sodium iodide symporter (NIS) gene delivery and to compare efficiency and tumor specificity with LPEI-PEG-GE11. Transfection of HCC cells with NIS cDNA, using G2-HD-OEI, resulted in a 44-fold increase in iodide uptake in vitro as compared with a 22-fold increase using LPEI-PEG-GE11. After intravenous application of G2-HD-OEI/NIS HCC tumors accumulated 6–11% ID/g 123I (percentage of the injected dose per gram tumor tissue) with an effective half-life of 10?hr (tumor-absorbed dose, 281?mGy/MBq) as measured by 123I scintigraphic gamma camera or single-photon emission computed tomography computed tomography (SPECT CT) imaging, as compared with 6.5–9% ID/g with an effective half-life of only 6?hr (tumor-absorbed dose, 47?mGy/MBq) for LPEI-PEG-GE11. After only two cycles of G2-HD-OEI/NIS/131I application, a significant delay in tumor growth was observed with markedly improved survival. A similar degree of therapeutic efficacy had been observed after four cycles of LPEI-PEG-GE11/131I. These results clearly demonstrate that biodegradable nanoparticles based on OEI-grafted oligoamines show increased efficiency for systemic NIS gene transfer in an HCC model with similar tumor selectivity as compared with LPEI-PEG-GE11, and therefore represent a promising strategy for NIS-mediated radioiodine therapy of HCC. PMID:21851208

Klutz, Kathrin; Willhauck, Michael J.; Dohmen, Christian; Wunderlich, Nathalie; Knoop, Kerstin; Zach, Christian; Senekowitsch-Schmidtke, Reingard; Gildehaus, Franz-Josef; Ziegler, Sibylle; Fürst, Sebastian; Göke, Burkhard; Wagner, Ernst

2011-01-01

83

Gene therapy for the inner ear  

PubMed Central

Animal studies on inner ear development, repair and regeneration provide understanding of molecular pathways that can be harnessed for treating inner ear disease. Use of transgenic mouse technology, in particular, has contributed knowledge of genes that regulate development of hair cells and innervation, and of molecular players that can induce regeneration, but this technology is not applicable for human treatment, for practical and ethical reasons. Therefore other means for influencing gene expression in the inner ear are needed. We describe several gene vectors useful for inner ear gene therapy and the practical aspects of introducing these vectors into the ear. We then review the progress toward using gene transfer for therapies in both auditory and balance systems, and discuss the technological milestones needed to advance to clinical application of these methods. PMID:23265411

Fukui, Hideto; Raphael, Yehoash

2012-01-01

84

Advance of Molecular Imaging Technology and Targeted Imaging Agent in Imaging and Therapy  

PubMed Central

Molecular imaging is an emerging field that integrates advanced imaging technology with cellular and molecular biology. It can realize noninvasive and real time visualization, measurement of physiological or pathological process in the living organism at the cellular and molecular level, providing an effective method of information acquiring for diagnosis, therapy, and drug development and evaluating treatment of efficacy. Molecular imaging requires high resolution and high sensitive instruments and specific imaging agents that link the imaging signal with molecular event. Recently, the application of new emerging chemical technology and nanotechnology has stimulated the development of imaging agents. Nanoparticles modified with small molecule, peptide, antibody, and aptamer have been extensively applied for preclinical studies. Therapeutic drug or gene is incorporated into nanoparticles to construct multifunctional imaging agents which allow for theranostic applications. In this review, we will discuss the characteristics of molecular imaging, the novel imaging agent including targeted imaging agent and multifunctional imaging agent, as well as cite some examples of their application in molecular imaging and therapy. PMID:24689058

Chen, Zhi-Yi; Wang, Yi-Xiang; Lin, Yan; Zhang, Jin-Shan; Yang, Feng; Zhou, Qiu-Lan; Liao, Yang-Ying

2014-01-01

85

Physical Principles of Microbubbles for Ultrasound Imaging and Therapy  

Microsoft Academic Search

Microbubble ultrasound contrast agents have been in clinical use for more than two decades, during which time their range of applications has increased to encompass echocardiography, Doppler enhancement, perfusion studies and molecular imaging, as well as a number of therapeutic applications including drug delivery, gene therapy, high-intensity focused ultrasound treatments and sonothrombolysis. The aim of this article is to review

Eleanor Stride

2009-01-01

86

Cell and Gene Therapies for Refractory Epilepsy  

PubMed Central

Despite recent advances in the development of antiepileptic drugs, refractory epilepsy remains a major clinical problem affecting up to 35% of patients with partial epilepsy. Currently, there are few therapies that affect the underlying disease process. Therefore, novel therapeutic concepts are urgently needed. The recent development of experimental cell and gene therapies may offer several advantages compared to conventional systemic pharmacotherapy: (i) Specificity to underlying pathogenetic mechanisms by rational design; (ii) specificity to epileptogenic networks by focal delivery; and (iii) avoidance of side effects. A number of naturally occurring brain substances, such as GABA, adenosine, and the neuropeptides galanin and neuropeptide Y, may function as endogenous anticonvulsants and, in addition, may interact with the process of epileptogenesis. Unfortunately, the systemic application of these compounds is compromised by limited bioavailability, poor penetration of the blood-brain barrier, or the widespread systemic distribution of their respective receptors. Therefore, in recent years a new field of cell and gene-based neuropharmacology has emerged, aimed at either delivering endogenous anticonvulsant compounds by focal intracerebral transplantation of bioengineered cells (ex vivo gene therapy), or by inducing epileptogenic brain areas to produce these compounds in situ (in vivo gene therapy). In this review, recent efforts to develop GABA-, adenosine-, galanin-, and neuropeptide Y- based cell and gene therapies are discussed. The neurochemical rationales for using these compounds are discussed, the advantages of focal applications are highlighted and preclinical cell transplantation and gene therapy studies are critically evaluated. Although many promising data have been generated recently, potential problems, such as long-term therapeutic efficacy, long-term safety, and efficacy in clinically relevant animal models, need to be addressed before clinical applications can be contemplated. PMID:18615179

Detlev, Boison

2007-01-01

87

ORIGINAL ARTICLE Retinoschisin gene therapy in photoreceptors, Mller glia  

E-print Network

ORIGINAL ARTICLE Retinoschisin gene therapy in photoreceptors, Müller glia or all retinal cells to the importance of cell targeting and appropriate vector choice in the success of retinal gene therapies. Gene of this recessive monogenic disease is well understood, it is an excellent candidate for gene augmenta- tion therapy

Schaffer, David V.

88

Vectors of Gene Therapy KATHERINE PARKER PONDER, M.D.  

E-print Network

CHAPTER 4 Vectors of Gene Therapy KATHERINE PARKER PONDER, M.D. INTRODUCTION Currently, gene therapy refers to the transfer of a gene that encodes a functional protein into a cell or the transfer that direct RNA processing such as polyadenylation. A second class of gene therapy involves altering

Ponder, Katherine P.

89

Genome editing for human gene therapy.  

PubMed

The rapid advancement of genome-editing techniques holds much promise for the field of human gene therapy. From bacteria to model organisms and human cells, genome editing tools such as zinc-finger nucleases (ZNFs), TALENs, and CRISPR/Cas9 have been successfully used to manipulate the respective genomes with unprecedented precision. With regard to human gene therapy, it is of great interest to test the feasibility of genome editing in primary human hematopoietic cells that could potentially be used to treat a variety of human genetic disorders such as hemoglobinopathies, primary immunodeficiencies, and cancer. In this chapter, we explore the use of the CRISPR/Cas9 system for the efficient ablation of genes in two clinically relevant primary human cell types, CD4+ T cells and CD34+ hematopoietic stem and progenitor cells. By using two guide RNAs directed at a single locus, we achieve highly efficient and predictable deletions that ablate gene function. The use of a Cas9-2A-GFP fusion protein allows FACS-based enrichment of the transfected cells. The ease of designing, constructing, and testing guide RNAs makes this dual guide strategy an attractive approach for the efficient deletion of clinically relevant genes in primary human hematopoietic stem and effector cells and enables the use of CRISPR/Cas9 for gene therapy. PMID:25398345

Meissner, Torsten B; Mandal, Pankaj K; Ferreira, Leonardo M R; Rossi, Derrick J; Cowan, Chad A

2014-01-01

90

Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles  

E-print Network

Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles Sharon States of America Abstract Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral

Schaffer, David V.

91

MOLECULAR THERAPY Vol. 4, No. 3, September 2001 Copyright The American Society of Gene Therapy  

E-print Network

MOLECULAR THERAPY Vol. 4, No. 3, September 2001 Copyright © The American Society of Gene Therapy. Barnes,5 Jesus Gomez-Navarro,1 David T. Curiel,1 and Ronald D. Alvarez5 1 The Gene Therapy Center, Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, 2 Department of Radiology

Hemminki, Akseli

92

ORTHOPAEDIC GENE THERAPY – LOST IN TRANSLATION?  

PubMed Central

Orthopaedic gene therapy has been the topic of considerable research for two decades. The preclinical data are impressive and many orthopaedic conditions are well suited to genetic therapies. But there have been few clinical trials and no FDA-approved product exists. This paper examines why this is so. The reasons are multifactorial. Clinical translation is expensive and difficult to fund by traditional academic routes. Because gene therapy is viewed as unsafe and risky, it does not attract major funding from the pharmaceutical industry. Start-up companies are burdened by the complex intellectual property environment and difficulties in dealing with the technology transfer offices of major universities. Successful translation requires close interactions between scientists, clinicians and experts in regulatory and compliance issues. It is difficult to create such a favourable translational environment. Other promising fields of biological therapy have contemplated similar frustrations approximately 20 years after their founding, so there seem to be more general constraints on translation that are difficult to define. Gene therapy has noted some major clinical successes in recent years, and a sense of optimism is returning to the field. We hope that orthopaedic applications will benefit collaterally from this upswing and move expeditiously into advanced clinical trials. PMID:21948071

Evans, C.H.; Ghivizzani, S.C.; Robbins, P.D.

2011-01-01

93

Radiopharmaceutical and Gene Therapy Program  

SciTech Connect

The objective of our research program was to determine whether novel receptors can be induced in solid cancers as a target for therapy with radiolabeled unmodified peptides that bind to the receptors. The hypothesis was that induction of a high number of receptors on the surface of these cancer cells would result in an increased uptake of the radiolabeled monomeric peptides as compared to published results with radiolabeled antibodies or peptides to naturally expressed antigens or receptors, and therefore a better therapeutic outcome. The following is a summary of published results.

Buchsbaum, Donald J.

2006-02-09

94

Gene therapy targeting to tumor endothelium  

Microsoft Academic Search

Tumor-associated vasculature is a relatively accessible component of solid cancers that is essential for tumor survival and growth, providing a vulnerable target for cancer gene therapy administered by intravenous injection. Several features of tumor-associated vasculature are different from normal vasculature, including overexpression of receptors for angiogenic growth factors, markers of vasculogenesis, upregulation of coagulation cascades, aberrant expression of adhesion molecules

M Bazan-Peregrino; L W Seymour; A L Harris

2007-01-01

95

Foamy Virus Vectors for HIV Gene Therapy  

PubMed Central

Highly active antiretroviral therapy (HAART) has vastly improved outcomes for patients infected with HIV, yet it is a lifelong regimen that is expensive and has significant side effects. Retroviral gene therapy is a promising alternative treatment for HIV/AIDS; however, inefficient gene delivery to hematopoietic stem cells (HSCs) has so far limited the efficacy of this approach. Foamy virus (FV) vectors are derived from non-pathogenic viruses that are not endemic to the human population. FV vectors have been used to deliver HIV-inhibiting transgenes to human HSCs, and they have several advantages relative to other retroviral vectors. These include an attractive safety profile, broad tropism, a large transgene capacity, and the ability to persist in quiescent cells. In addition, the titers of FV vectors are not reduced by anti-HIV transgenes that affect the production of lentivirus (LV) vectors. Thus FV vectors are very promising for anti-HIV gene therapy. This review covers the advantages of FV vectors and describes their preclinical development for anti-HIV gene therapy. PMID:24153061

Olszko, Miles E.; Trobridge, Grant D.

2013-01-01

96

The Dangerous Promise of Gene Therapy  

NSDL National Science Digital Library

The issue-focused, peer-reviewed article investigates the first death of a participant in a gene therapy experiment. It reveals: lack of informed consent by participants, questionable use of volunteer types for trials, inadequate governmental and institutional controls, and doctors with conflict-of-interest agendas.

Sophia Kolehmainen (Council for Responsible Genetics;)

2000-02-01

97

Gene Tests May Improve Therapy for Endometrial Cancer  

MedlinePLUS

... External link, please review our exit disclaimer . Subscribe Gene Tests May Improve Therapy for Endometrial Cancer By analyzing genes in hundreds of endometrial tumors, scientists identified details ...

98

Identity and the ethics of gene therapy.  

PubMed

Some conditions detrimental to human well-being, such as sickle-cell anaemia, cystic fibrosis, muscular dystrophy, Lesch-Nyhan disease and various immunodeficiencies, are genetically determined. One potential means of preventing the development of such conditions is the manipulation of genetic material in the conceptus of an organism which would otherwise develop such conditions. Genetic manipulations could take the form either of excising and substituting genetic material, excising but not substituting genetic material, adding but not excising genetic material or reorganizing existing genetic material. To succeed, manipulation would have to change genetic structure so as to change its informational content. It might be thought, however, that all or some such manipulations would involve causing particular individuals to cease to exist and involve bringing into existence new, distinct individuals. Gene therapy could not, therefore, be a procedure which improved the circumstances of the particular individual to whom it is applied. It might be suggested that once the metaphysics of identity and the facts of gene therapy are understood, certain interesting conclusions concerning the ethics of gene therapy emerge. Some such conclusions have been discussed in this journal by Noam J. Zohar and Jeffrey P. Kahn. More, however, needs to be said about them since neither Zohar nor Kahn draws the correct conclusions. While both have pertinent things to say, neither has given a completely clear account of the metaphysics of gene therapy and so neither has completely traced out the implication of the metaphysics for the ethics of gene therapy. This paper attempts to remedy these defects. PMID:11654027

Elliot, Robert

1993-01-01

99

Gene-Directed Enzyme Prodrug Therapy.  

PubMed

As one targeting strategy of prodrug delivery, gene-directed enzyme prodrug therapy (GDEPT) promises to realize the targeting through its three key features in cancer therapy-cell-specific gene delivery and expression, controlled conversion of prodrugs to drugs in target cells, and expanded toxicity to the target cells' neighbors through bystander effects. After over 20 years of development, multiple GDEPT systems have advanced into clinical trials. However, no GDEPT product is currently marketed as a drug, suggesting that there are still barriers to overcome before GDEPT becomes a standard therapy. In this review, we first provide a general introduction of this prodrug targeting strategy. Then, we utilize the four most thoroughly studied systems to illustrate components, mechanisms, preclinical and clinical results, and further development directions of GDEPT. These four systems are herpes simplex virus thymidine kinase/ganciclovir, cytosine deaminase/5-fluorocytosine, cytochrome P450/oxazaphosphorines, and nitroreductase/CB1954 system. Later, we focus our discussion on bystander effects including local and distant bystander effects. Lastly, we discuss carriers that are used to deliver genes for GDEPT including virus carriers and non-virus carriers. Among these carriers, the stem cell-based gene delivery system represents one of the newest carriers under development, and may brought about a breakthrough to the gene delivery issue of GDEPT. PMID:25338741

Zhang, Jin; Kale, Vijay; Chen, Mingnan

2014-10-23

100

Methods to improve cardiac gene therapy expression.  

PubMed

Gene therapy strategies are becoming a valuable approach for the treatment of heart failure. Some trials are ongoing and others are being organized. Vascular access in clinical experimentation is still the chosen modality of delivery, but many other approaches are in research and development. A successful gene therapy strategy involves not only the choice of the right vector and gene, but also the correct delivery strategy that allows for transduction of the highest percentage of cardiomyocytes, limited spilling of virus into other organs and the possibility to correlate the amount of injected virus to the rate of the expression within the cardiac tissue. The authors will first concentrate on clarifying what the barriers are that the virus has to overcome in order to reach the nuclei of the target organs and methodologies that have been tested to improve the range of expression. PMID:25340284

Scimia, Maria Cecilia; Sydnes, Kate E; Zuppo, Daniel A; Koch, Walter J

2014-11-01

101

Contributions of Gene Marking to Cell and Gene Therapies  

PubMed Central

Abstract The first human genetic modification studies used replication-incompetent integrating vector vectors to introduce marker genes into T lymphocytes and subsequently into hematopoietic stem cells. Such studies have provided numerous insights into the biology of hematopoiesis and immune reconstitution and contributed to clinical development of gene and cell therapies. Tracking of hematopoietic reconstitution and analysis of the origin of residual malignant disease after hematopoietic transplantation has been possible via gene marking. Introduction of selectable marker genes has enabled preselection of specific T-cell populations for tumor and viral immunotherapy and reduced the threat of graft-versus-host disease, improving the survival of patients after allogeneic marrow transplantation. Marking studies in humans, murine xenografts, and large animals have helped optimize conditions for gene transfer into CD34+ hematopoietic progenitors, contributing to the achievement of gene transfer efficiencies sufficient for clinical benefit in several serious genetic diseases such as X-linked severe combined immunodeficiency and adrenoleukodystropy. When adverse events linked to insertional mutagenesis arose in clinical gene therapy trials for inherited immunodeficiencies, additional animal studies using gene-marking vectors have greatly increased our understanding of genotoxicity. The knowledge gained from these studies is being translated into new vector designs and clinical protocols, which we hope will continue to improve the efficiency, effectiveness and safety of these promising therapeutic approaches. PMID:21261461

Barese, Cecilia N.

2011-01-01

102

Gene Therapy: Implications for Craniofacial Regeneration  

PubMed Central

Gene therapy in the craniofacial region provides a unique tool for delivery of DNA to coordinate protein production in both time and space. The drive to bring this technology to the clinic is derived from the fact that over 85% of the global population may at one time require repair or replacement of a craniofacial structure. This need ranges from mild tooth decay and tooth loss to temporomandibular joint disorders and large-scale reconstructive surgery. Our ability to insert foreign DNA into a host cell has been developing since early uses of gene therapy to alter bacterial properties for waste cleanup in the 1980s followed by successful human clinical trials in the 1990s to treat severe combined immunodeficiency. In the past twenty years the emerging field of craniofacial tissue engineering has adopted these techniques to enhance regeneration of mineralized tissues, salivary gland, periodontium, and to reduce tumor burden of head and neck squamous cell carcinoma. Studies are currently pursuing research on both biomaterial-mediated gene delivery as well as more clinically efficacious, though potentially more hazardous, viral methods. Though hundreds of gene therapy clinical trials have taken place in the past twenty years, we must still work to ensure an ideal safety profile for each gene and delivery method combination. With adequate genotoxicity testing, we can expect gene therapy to augment protein delivery strategies and potentially allow for tissue-specific targeting, delivery of multiple signals, and increased spatial and temporal control with the goal of natural tissue replacement in the craniofacial complex. PMID:22337437

Scheller, Erica L.; Villa-Diaz, Luis G; Krebsbach, Paul H.

2011-01-01

103

Microfluidic approaches for gene delivery and gene therapy Jungkyu Kim,a  

E-print Network

Microfluidic approaches for gene delivery and gene therapy Jungkyu Kim,a Inseong Hwang,b Derek for gene delivery and therapy. The micro-scaled environment within microfluidic systems enables precise are producing increased efficiency in gene delivery and promise improved gene therapy results. Introduction Many

Sun, Yu

104

Theranostic agents for intracellular gene delivery with spatiotemporal imaging  

PubMed Central

Gene therapy is the modification of gene expression to treat a disease. However, efficient intracellular delivery and monitoring of gene therapeutic agents is an ongoing challenge. Use of theranostic agents with suitable targeted, controlled delivery and imaging modalities has the potential to greatly advance gene therapy. Inorganic nanoparticles including magnetic nanoparticles, gold nanoparticles, and quantum dots have been shown to be effective theranostic agents for the delivery and spatiotemporal tracking of oligonucleotides in vitro and even a few cases in vivo. Major concerns remain to be addressed including cytotoxicity, particularly of quantum dots; effective dosage of nanoparticles for optimal theranostic effect; development of real-time in vivo imaging; and further improvement of gene therapy efficacy. PMID:23606894

Knipe, Jennifer M.; Peters, Jonathan T.; Peppas, Nicholas A.

2013-01-01

105

MINI REVIEW MODIFIED ADENOVIRUSES FOR CANCER GENE THERAPY  

E-print Network

MINI REVIEW MODIFIED ADENOVIRUSES FOR CANCER GENE THERAPY Anna KANERVA 1­3 and Akseli HEMMINKI 1,2 * 1 Cancer Gene Therapy Group, Rational Drug Design, Biomedicum Helsinki, University of Helsinki of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland Adenoviral gene therapy

Hemminki, Akseli

106

Gene Therapy for Protein C Deficiency 2831 J. Clin. Invest.  

E-print Network

Gene Therapy for Protein C Deficiency 2831 J. Clin. Invest. © The American Society for Clinical://www.jci.org Therapeutic Levels of Human Protein C in Rats after Retroviral Vector-mediated Hepatic Gene Therapy Shi that would prevent purpura fulminans, and that hepatic gene therapy might become a viable treatment

Ponder, Katherine P.

107

The American Society of Gene Therapy original article  

E-print Network

© The American Society of Gene Therapy original article Molecular Therapy vol. 15 no. 12, 2107 the way for HR-based strategies in gene therapy.8 On the basis of the achievements and setbacks in some gene through its endogenous promoter. We have developed a novel system based on integrase

Cai, Long

108

Transcriptional Targeting for Ovarian Cancer Gene Therapy E. Casado,*,  

E-print Network

REVIEW Transcriptional Targeting for Ovarian Cancer Gene Therapy E. Casado,*, D. M. Nettelbeck. Alvarez,,¶ and D. T. Curiel*, ,1 *Division of Human Gene Therapy, Department of Medicine, Department/Gynecology; §Department of Pathology, Department of Cell Biology, and Department of Surgery; Gene Therapy Center

Hemminki, Akseli

109

Newer gene editing technologies toward HIV gene therapy.  

PubMed

Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called "Berlin patient" who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy. PMID:24284874

Manjunath, N; Yi, Guohua; Dang, Ying; Shankar, Premlata

2013-11-01

110

Newer Gene Editing Technologies toward HIV Gene Therapy  

PubMed Central

Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called “Berlin patient” who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy. PMID:24284874

Manjunath, N.; Yi, Guohua; Dang, Ying; Shankar, Premlata

2013-01-01

111

Suicide Gene Therapy for Cancer – Current Strategies  

PubMed Central

Current cancer treatments may create profound iatrogenic outcomes. The adverse effects of these treatments still remain, as the serious problems that practicing physicians have to cope with in clinical practice. Although, non-specific cytotoxic agents constitute an effective treatment modality against cancer cells, they also tend to kill normal, quickly dividing cells. On the other hand, therapies targeting the genome of the tumors are both under investigation, and some others are already streamlined to clinical practice. Several approaches have been investigated in order to find a treatment targeting the cancer cells, while not affecting the normal cells. Suicide gene therapy is a therapeutic strategy, in which cell suicide inducing transgenes are introduced into cancer cells. The two major suicide gene therapeutic strategies currently pursued are: cytosine deaminase/5-fluorocytosine and the herpes simplex virus/ganciclovir. The novel strategies include silencing gene expression, expression of intracellular antibodies blocking cells’ vital pathways, and transgenic expression of caspases and DNases. We analyze various elements of cancer cells’ suicide inducing strategies including: targets, vectors, and mechanisms. These strategies have been extensively investigated in various types of cancers, while exploring multiple delivery routes including viruses, non-viral vectors, liposomes, nanoparticles, and stem cells. We discuss various stages of streamlining of the suicide gene therapy into clinical oncology as applied to different types of cancer. Moreover, suicide gene therapy is in the center of attention as a strategy preventing cancer from developing in patients participating in the clinical trials of regenerative medicine. In oncology, these clinical trials are aimed at regenerating, with the aid of stem cells, of the patients’ organs damaged by pathologic and/or iatrogenic factors. However, the stem cells carry the risk of neoplasmic transformation. We discuss cell suicide inducing strategies aimed at preventing stem cell-originated cancerogenesis. PMID:24294541

Zarogoulidis, Paul; Darwiche, Kaid; Sakkas, Antonios; Yarmus, Lonny; Huang, Haidong; Li, Qiang; Freitag, Lutz; Zarogoulidis, Konstantinos; Malecki, Marek

2013-01-01

112

Bacterial Systems for Tumor-Specific Gene Therapy  

Microsoft Academic Search

This chapter describes the power of genetically engineered bacteria in cancer therapy. In the applications we consider, the\\u000a bacteria are genetically engineered to carry a specific gene into tumors, and on this basis, it can be considered gene therapy.\\u000a However, if gene therapy is defined as the introduction of a gene, or part of a gene, into the cancer cells

J. Martin Brown; Shie-Chau Liu; Jan Theys; Philippe Lambin

113

Proton Therapy Verification with PET Imaging  

PubMed Central

Proton therapy is very sensitive to uncertainties introduced during treatment planning and dose delivery. PET imaging of proton induced positron emitter distributions is the only practical approach for in vivo, in situ verification of proton therapy. This article reviews the current status of proton therapy verification with PET imaging. The different data detecting systems (in-beam, in-room and off-line PET), calculation methods for the prediction of proton induced PET activity distributions, and approaches for data evaluation are discussed. PMID:24312147

Zhu, Xuping; Fakhri, Georges El

2013-01-01

114

Germline alteration by gene therapy: assessing and reducing the risks.  

PubMed

Developments in gene therapy are certain to lead to the treatment of an increasing variety of diseases, some of which will affect patients who might wish to have children following their gene therapy treatment. These circumstances raise the concern that germline integration of gene therapy vector DNA could occur. Although our current understanding of reproductive biology and of the biodistribution of gene therapy vectors administered to extragonadal sites indicate that this risk is low, animal experiments and clinical studies designed specifically to address this question are warranted; because of this risk, every gene therapy vector should be tested for its potential to integrate into germ cells and preimplantation embryos. PMID:9857365

Gordon, J W

1998-11-01

115

original article The American Society of Gene & Cell Therapy Molecular Therapy 1  

E-print Network

original article© The American Society of Gene & Cell Therapy Molecular Therapy 1 publication 16 November 2010. doi:10.1038/mt.2010.249 IntroductIon The ultimate goal of gene therapy (IDUA) gene resulting in inactivation of the IDUA enzyme. The loss of IDUA protein results

Ford, James

116

Gene therapy approaches for spinal cord injury  

NASA Astrophysics Data System (ADS)

As the biomedical engineering field expands, combination technologies are demonstrating enormous potential for treating human disease. In particular, intersections between the rapidly developing fields of gene therapy and tissue engineering hold promise to achieve tissue regeneration. Nonviral gene therapy uses plasmid DNA to deliver therapeutic proteins in vivo for extended periods of time. Tissue engineering employs biomedical materials, such as polymers, to support the regrowth of injured tissue. In this thesis, a combination strategy to deliver genes and drugs in a polymeric scaffold was applied to a spinal cord injury model. In order to develop a platform technology to treat spinal cord injury, several nonviral gene delivery systems and polymeric scaffolds were evaluated in vitro and in vivo. Nonviral vector trafficking was evaluated in primary neuronal culture to develop an understanding of the barriers to gene transfer in neurons and their supporting glia. Although the most efficient gene carrier in vitro differed from the optimal gene carrier in vivo, confocal and electron microscopy of these nonviral vectors provided insights into the interaction of these vectors with the nucleus. A novel pathway for delivering nanoparticles into the nuclei of neurons and Schwann cells via vesicle trafficking was observed in this study. Reporter gene expression levels were evaluated after direct and remote delivery to the spinal cord, and the optimal nonviral vector, dose, and delivery strategy were applied to deliver the gene encoding the basic fibroblast growth factor (bFGF) to the spinal cord. An injectable and biocompatible gel, composed of the amphiphillic polymer poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG) was evaluated as a drug and gene delivery system in vitro, and combined with the optimized nonviral gene delivery system to treat spinal cord injury. Plasmid DNA encoding the bFGF gene and the therapeutic NEP1--40 peptide were incorporated in the PEG-PCL-PEG gel and injected into a lesion transecting the main dorsomedial and minor ventral medial corticospinal tract (CST). The degree of collateralization of the transected CST was quantified as an indicator of the regenerative potential of these treatments. At one month post-injury, we observed the robust rostral collateralization of the CST tract in response to the bFGF plasmid-loaded gel. In conclusion, we hope that this platform technology can be applied to the sustained local delivery of other proteins for the treatment of spinal cord injury.

Bright, Corinne

117

Restorative gene therapy approaches to Parkinson's disease.  

PubMed

Perhaps one of the most exciting developments in brain research of the past decade is the advent of genetic intervention in human neurologic disease. Although there are a variety of gene transfer approaches, none of which has been perfected, gene therapy is now science fact and no longer science fiction. As technology progresses, some vectors will prove more effective for certain disease categories than others; it is too early to predict definitively which vector would be most effective for therapy in Parkinson's disease and other movement disorders. Nonetheless, it is likely that within the next year or two a gene therapy trial will be instituted in human patients with Parkinson's disease. The potential for an impact on the symptoms and progression of this disease is significant. Clinicians may be on the threshold of a new era of intervention for Parkinson's disease and other neurologic diseases, based on bypassing traditional but less selective drug-extracellular receptor interactions and instead focusing on genetic modulation of specific intracellular processes. The continuing development of small incremental changes of new dopamine agonists and pharmacologic agents will likely pale in comparison to the specificity of intracellular genetic manipulation. PMID:10093593

Freese, A

1999-03-01

118

Root images of healing in dance therapy  

Microsoft Academic Search

Dance therapy is both a modern and an ancient art of healing. For modern dance therapists, the understanding and practice of healing practices is enriched with echoes of ancient images and practices. These echoes provide both humility and perspective on practices carried out in mental health clinics, nursing homes, schools, and other settings today. “Root images” in this paper will

Ilene Serlin

1993-01-01

119

Gene-modified bone marrow cell therapy for prostate cancer  

Microsoft Academic Search

There is a critical need to develop new and effective cancer therapies that target bone, the primary metastatic site for prostate cancer and other malignancies. Among the various therapeutic approaches being considered for this application, gene-modified cell-based therapies may have specific advantages. Gene-modified cell therapy uses gene transfer and cell-based technologies in a complementary fashion to chaperone appropriate gene expression

H Wang; T C Thompson

2008-01-01

120

Nucleic acid immunization: a prophylactic gene therapy?  

PubMed

Nucleic acid (NA) vaccines may offer the safety of subunit or inactivated vaccines and, at the same time, provide the advantages of live recombinant vaccines, such as induction of a protective cellular immune response. In Germany, the so-called 'Gene Law' regulates the genetic modification of organisms such as prokaryotic or eukaryotic cells for the construction of recombinant NAs intended for use as NA vaccines. Neither NAs nor human beings treated with NAs are subject to Gene Law regulations but preclinical laboratory experiments are regulated by the Gene Law. Gene therapy, as defined in a recent draft of a European guideline for the production of gene therapeutics, includes the genetic modification of human somatic cells via transfer of NAs and thus includes NA vaccines. The guideline provides recommendations for the production of NA vaccines for human use and for preclinical safety testing. NA vaccines are products derived by biotechnological processes, as defined in part A of the annex of Council Regulation (EEC) No. 2309/93 of 22 July 1993. Applications for marketing authorization in Member States of the European Union will thus be reviewed by the European Agency for the Evaluation of Medicinal Products starting from 1 January 1995. Inoculation of NAs encompassing a full-length but int/nef-defective simian immunodeficiency provirus allowing limited replication of viruses released is being investigated at the Paul-Ehrlich-Institute as a model for a NA vaccine against AIDS.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7879417

Cichutek, K

1994-12-01

121

A realistic chance for gene therapy in the near future  

Microsoft Academic Search

The expanding knowledge of the genetic and cellular mechanisms of human diseases in the post-genomic era coupled with the development of different vector systems to efficiently transfer genes to a variety of cell types and organs in vivo gave rise to the concept of gene therapy as a promising therapeutic option for genetic and acquired diseases. Gene therapy has been

Stefan Worgall

2005-01-01

122

Gene therapy: Into the home stretch  

SciTech Connect

Tumors cannot live without blood. Shut off the blood vessels that feed a tumor and the tumor will turn black and shrivel away. That simple idea lies behind the first attempt to cure a disease by gene therapy, expected to take place at the National Cancer Institute in the next few weeks. When it does, it will test a technique that worked like a charm in mice. When a potent natural killer called tumor necrosis factor, or TNF, is injected into the bloodstream of mice, it begins to shrink tumors within hours, sometimes even minutes. But so far, attempts to recreate that miracle in people with cancer have not fared as well. TNF has been given intravenously to more than 35 patients in experiments that were a failure. Researchers hope to deliver TNF in much larger doses directly to a tumor by packaging the gene for TNF inside special lymphocytes that have a natural affinity for cancer.

Culliton, B.J.

1990-08-31

123

Gene therapy in animal models of autosomal dominant retinitis pigmentosa  

PubMed Central

Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success. PMID:23077406

Rossmiller, Brian; Mao, Haoyu

2012-01-01

124

Improved animal models for testing gene therapy for atherosclerosis.  

PubMed

Gene therapy delivered to the blood vessel wall could augment current therapies for atherosclerosis, including systemic drug therapy and stenting. However, identification of clinically useful vectors and effective therapeutic transgenes remains at the preclinical stage. Identification of effective vectors and transgenes would be accelerated by availability of animal models that allow practical and expeditious testing of vessel-wall-directed gene therapy. Such models would include humanlike lesions that develop rapidly in vessels that are amenable to efficient gene delivery. Moreover, because human atherosclerosis develops in normal vessels, gene therapy that prevents atherosclerosis is most logically tested in relatively normal arteries. Similarly, gene therapy that causes atherosclerosis regression requires gene delivery to an existing lesion. Here we report development of three new rabbit models for testing vessel-wall-directed gene therapy that either prevents or reverses atherosclerosis. Carotid artery intimal lesions in these new models develop within 2-7 months after initiation of a high-fat diet and are 20-80 times larger than lesions in a model we described previously. Individual models allow generation of lesions that are relatively rich in either macrophages or smooth muscle cells, permitting testing of gene therapy strategies targeted at either cell type. Two of the models include gene delivery to essentially normal arteries and will be useful for identifying strategies that prevent lesion development. The third model generates lesions rapidly in vector-naïve animals and can be used for testing gene therapy that promotes lesion regression. These models are optimized for testing helper-dependent adenovirus (HDAd)-mediated gene therapy; however, they could be easily adapted for testing of other vectors or of different types of molecular therapies, delivered directly to the blood vessel wall. Our data also supports the promise of HDAd to deliver long-term therapy from vascular endothelium without accelerating atherosclerotic disease. PMID:24528162

Du, Liang; Zhang, Jingwan; De Meyer, Guido R Y; Flynn, Rowan; Dichek, David A

2014-04-01

125

Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients  

PubMed Central

BACKGROUND. Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMThi). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome. METHODS. We enrolled 7 newly diagnosed glioblastoma patients with MGMThi tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O6BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated. RESULTS. Gene therapy permitted a significant increase in the mean number of tolerated O6BG/TMZ cycles (4.4 cycles per patient, P < 0.05) compared with historical controls without gene therapy (n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5–57+) months and OS of 20 (range 13–57+) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O6BG. CONCLUSION. These data support further development of chemoprotective gene therapy in combination with O6BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT. TRIAL REGISTRATION. Clinicaltrials.gov NCT00669669. FUNDING. R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970. PMID:25105369

Adair, Jennifer E.; Johnston, Sandra K.; Mrugala, Maciej M.; Beard, Brian C.; Guyman, Laura A.; Baldock, Anne L.; Bridge, Carly A.; Hawkins-Daarud, Andrea; Gori, Jennifer L.; Born, Donald E.; Gonzalez-Cuyar, Luis F.; Silbergeld, Daniel L.; Rockne, Russell C.; Storer, Barry E.; Rockhill, Jason K.; Swanson, Kristin R.; Kiem, Hans-Peter

2014-01-01

126

Heat-induced Gene Expression as a Novel Targeted Cancer Gene Therapy Strategy1  

Microsoft Academic Search

One of the main advantages of gene therapy over traditional therapy is the potential to target the expression of therapeutic genes in desired cells or tissues. To achieve targeted gene expression, we experimented with a new approach based on the long-established phenomenon of the heat shock response. By using the green fluorescence protein as a reporter gene, it was demonstrated

Qian Huang; Jim K. Hu; Frank Lohr; Li Zhang; Rod Braun; Jennifer Lanzen; John B. Little; Mark W. Dewhirst; Chuan-Yuan Li

2000-01-01

127

Interactive level set segmentation for image-guided therapy  

E-print Network

Image-guided therapy procedures require the patient to remain still throughout the image acquisition, data analysis and therapy. This imposes a tight time constraint on the over-all process. Automatic extraction of the ...

Kiryati, Nahum

128

Near-infrared light triggered photodynamic therapy in combination with gene therapy using upconversion nanoparticles for effective cancer cell killing  

NASA Astrophysics Data System (ADS)

Upconversion nanoparticles (UCNPs) have drawn much attention in cancer imaging and therapy in recent years. Herein, we for the first time report the use of UCNPs with carefully engineered surface chemistry for combined photodynamic therapy (PDT) and gene therapy of cancer. In our system, positively charged NaGdF4:Yb,Er UCNPs with multilayered polymer coatings are synthesized via a layer by layer strategy, and then loaded simultaneously with Chlorin e6 (Ce6), a photosensitizing molecule, and small interfering RNA (siRNA), which targets the Plk1 oncogene. On the one hand, under excitation by a near-infrared (NIR) light at 980 nm, which shows greatly improved tissue penetration compared with visible light, cytotoxic singlet oxygen can be generated via resonance energy transfer from UCNPs to photosensitizer Ce6, while the residual upconversion luminescence is utilized for imaging. On the other hand, the silencing of Plk1 induced by siRNA delivered with UCNPs could induce significant cancer cell apoptosis. As the result of such combined photodynamic and gene therapy, a remarkably enhanced cancer cell killing effect is realized. Our work thus highlights the promise of UCNPs for imaging guided combination therapy of cancer.Upconversion nanoparticles (UCNPs) have drawn much attention in cancer imaging and therapy in recent years. Herein, we for the first time report the use of UCNPs with carefully engineered surface chemistry for combined photodynamic therapy (PDT) and gene therapy of cancer. In our system, positively charged NaGdF4:Yb,Er UCNPs with multilayered polymer coatings are synthesized via a layer by layer strategy, and then loaded simultaneously with Chlorin e6 (Ce6), a photosensitizing molecule, and small interfering RNA (siRNA), which targets the Plk1 oncogene. On the one hand, under excitation by a near-infrared (NIR) light at 980 nm, which shows greatly improved tissue penetration compared with visible light, cytotoxic singlet oxygen can be generated via resonance energy transfer from UCNPs to photosensitizer Ce6, while the residual upconversion luminescence is utilized for imaging. On the other hand, the silencing of Plk1 induced by siRNA delivered with UCNPs could induce significant cancer cell apoptosis. As the result of such combined photodynamic and gene therapy, a remarkably enhanced cancer cell killing effect is realized. Our work thus highlights the promise of UCNPs for imaging guided combination therapy of cancer. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr02495h

Wang, Xin; Liu, Kai; Yang, Guangbao; Cheng, Liang; He, Lu; Liu, Yumeng; Li, Yonggang; Guo, Liang; Liu, Zhuang

2014-07-01

129

Viability of Long-Term Gene Therapy in the Cochlea  

PubMed Central

Gene therapy has been investigated as a way to introduce a variety of genes to treat neurological disorders. An important clinical consideration is its long-term effectiveness. This research aims to study the long-term expression and effectiveness of gene therapy in promoting spiral ganglion neuron survival after deafness. Adenoviral vectors modified to express brain derived neurotrophic factor or neurotrophin-3 were unilaterally injected into the guinea pig cochlea one week post ototoxic deafening. After six months, persistence of gene expression and significantly greater neuronal survival in neurotrophin-treated cochleae compared to the contralateral cochleae were observed. The long-term gene expression observed indicates that gene therapy is potentially viable; however the degeneration of the transduced cells as a result of the original ototoxic insult may limit clinical effectiveness. With further research aimed at transducing stable cochlear cells, gene therapy may be an efficacious way to introduce neurotrophins to promote neuronal survival after hearing loss. PMID:24751795

Atkinson, Patrick J.; Wise, Andrew K.; Flynn, Brianna O.; Nayagam, Bryony A.; Richardson, Rachael T.

2014-01-01

130

Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals  

Microsoft Academic Search

Reporter genes (eg ?-galactosidase, chloramphenicol-acetyltransferase, green fluorescent protein, luciferase) play critical roles in investigating mechanisms of gene expression in transgenic animals and in developing gene delivery systems for gene therapy. However, measuring expression of these reporter genes requires biopsy or death. We now report a procedure to image reporter gene expression repetitively and non-invasively in living animals with positron emission

D C MacLaren; S S Gambhir; N Satyamurthy; J R Barrio; S Sharfstein; T Toyokuni; L Wu; A J Berk; S R Cherry; M E Phelps; H R Herschman

1999-01-01

131

Gene Therapy Ameliorates Cardiovascular Disease in Dogs With Mucopolysaccharidosis VII  

E-print Network

Gene Therapy Ameliorates Cardiovascular Disease in Dogs With Mucopolysaccharidosis VII M.M. Sleeper;110:815-820.) Key Words: cardiovascular diseases gene therapy lysosomes mucopolysaccharidosis--Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient -glucuronidase (GUSB) activity

Ponder, Katherine P.

132

In Utero gene therapy: current challenges and perspectives  

Microsoft Academic Search

Over the past few years, considerable progress in prenatal diagnosis and surgery combined with improvements in vector design vindicate a reappraisal of the feasibility of in utero gene therapy for serious monogenetic diseases. As adult gene therapy gathers pace, several apparent obstacles to its application as a treatment may be overcome by pre- or early postnatal treatment. This review will

Simon N. Waddington; M. Gabriela Kramer; Ruben Hernandez-Alcoceba; Suzanne M. K. Buckley; Michael Themis; Charles Coutelle; Jesus Prieto

2005-01-01

133

Gene Therapy and Informed Consent Decision Making: Nursing Research Directions  

Microsoft Academic Search

Recent gene therapy clinical trials have demonstrated significant promise for treating a number of genetic neuromuscular disorders. Although nurses are experienced in educating patients and families about the benefits and risks of conventional therapeutics, there are significant challenges for guiding patients through the decision-making phase of gene therapy clinical trial participation. The first part of this review provides an overview

Rita W. Kaspar; Celia E. Wills; Brian K. Kaspar

2009-01-01

134

Prospects for Gene Therapy in the Fragile X Syndrome  

ERIC Educational Resources Information Center

Gene therapy is unarguably the definitive way to treat, and possibly cure, genetic diseases. A straightforward concept in theory, in practice it has proven difficult to realize, even when directed to easily accessed somatic cell systems. Gene therapy for diseases in which the central nervous system (CNS) is the target organ presents even greater…

Rattazzi, Mario C.; LaFauci, Giuseppe; Brown, W. Ted

2004-01-01

135

[Gene replacement therapy in achromatopsia type 2].  

PubMed

Achromatopsia is an autosomal recessive inherited retinal disease caused by a complete loss of cone photoreceptor function. About 80?% of achromatopsia patients show mutations in the alpha or beta subunit (A3 and B3) of the cGMP controlled cation channel CNG (cyclic nucleotide-gated channel) of cone photoreceptors. Homologous to the human disease, CNGA3 deficient mice reveal a loss of cone specific functionality leading to degeneration of affected cone photoreceptors. The Institute for Ophthalmic Research in Tübingen has now succeeded in curing achromatopsia ACHM2 in an animal model. In this article, we explain the recombinant adeno-associated virus-based approach in detail. Furthermore, applied non-invasive diagnostic techniques for quality and success control, ERG, SLO and OCT, are described. The success of the therapy is indicated by a restored cone photoreceptor function as well as the neuronal processing of retinal signals resulting in a specific, cone-mediated behaviour. The outstanding results derived from the animal model are the starting point for the first human translation of a gene therapy for achromatopsia in Germany. PMID:24658860

Mühlfriedel, R; Tanimoto, N; Seeliger, M W

2014-03-01

136

Large deformation 3D image registration in image-guided radiation therapy  

E-print Network

processing of serial 3D CT images used in image- guided radiation therapy. A major assumption in deformable methods, such as cone beam CT and CT-on-rails, that enable image guided radiation therapy as a way to meetLarge deformation 3D image registration in image-guided radiation therapy Mark Foskey, Brad Davis

Utah, University of

137

Gene Therapy in the Treatment of Heart Failure  

NSDL National Science Digital Library

Heart failure is a major cause of morbidity and mortality in contemporary societies. Although progress in conventional treatment modalities is making steady and incremental gains to reduce this disease burden, there remains a need to explore new and potentially therapeutic approaches. Gene therapy, for example, was initially envisioned as a treatment strategy for inherited monogenic disorders. It is now apparent that gene therapy has broader potential that also includes acquired polygenic diseases, such as heart failure. Advances in the understanding of the molecular basis of conditions such as these, together with the evolution of increasingly efficient gene transfer technology, has placed congestive heart failure within reach of gene-based therapy.

2007-04-01

138

Nanoarchitectonics in cancer therapy and imaging diagnosis.  

PubMed

Nanoarchitectonics has gained remarkable importance due to the fabrication of various recent nanostructures with the capability of being used in biomedical science, particularly in cancer diagnosis and treatment. These nanosized structures possess unique physical and optical properties that can be exploited for cancer therapeutics, and so nanoarchitectonics is popularly known as nanomedicine. The goal of this review is to discuss the latest findings in nanostructures research including nanocrystals, nanotubes, nanoshells, nanopillars, nanoballs, nanoflowers, nanorods, nanocontainers, nanobelts, nanocages, nanodiscs, nanodots, nanoprisms, nanoplates, nanorings, nanocubes, nanobranches, nanospheres, nanorattles, nanostars, nanotrees, nanowires, nanowalls, nanodiamonds, nanosheets, layered nanostructures, quantum dots, mesoporous nanostructures etc. in the field of cancer therapy and imaging. This review further highlights brief information about use of radionuclide in cancer. Lastly, different nanoformulations that are available in the market or are under clinical trials for cancer therapy and imaging are discussed. PMID:24730301

Pandey, Abhijeet P; Girase, Nayandip M; Patil, Mahendra D; Patil, Pravin O; Patil, Dilip A; Deshmukh, Prashant K

2014-01-01

139

Gene therapy for cardiovascular disease mediated by ultrasound and microbubbles  

PubMed Central

Gene therapy provides an efficient approach for treatment of cardiovascular disease. To realize the therapeutic effect, both efficient delivery to the target cells and sustained expression of transgenes are required. Ultrasound targeted microbubble destruction (UTMD) technique has become a potential strategy for target-specific gene and drug delivery. When gene-loaded microbubble is injected, the ultrasound-mediated microbubble destruction may spew the transported gene to the targeted cells or organ. Meanwhile, high amplitude oscillations of microbubbles increase the permeability of capillary and cell membrane, facilitating uptake of the released gene into tissue and cell. Therefore, efficiency of gene therapy can be significantly improved. To date, UTMD has been successfully investigated in many diseases, and it has achieved outstanding progress in the last two decades. Herein, we discuss the current status of gene therapy of cardiovascular diseases, and reviewed the progress of the delivery of genes to cardiovascular system by UTMD. PMID:23594865

2013-01-01

140

77 FR 71194 - Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...  

Federal Register 2010, 2011, 2012, 2013

...guidance are cellular therapy, gene therapy, therapeutic vaccination, and xenotransplantation. The guidance is intended to clarify...guidance are cellular therapy, gene therapy, therapeutic vaccination, and xenotransplantation. The guidance is intended to...

2012-11-29

141

78 FR 70307 - Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...  

Federal Register 2010, 2011, 2012, 2013

...guidance are cellular therapy, gene therapy, therapeutic vaccination, xenotransplantation, and certain biologic-device combination...guidance include cellular therapy, gene therapy, therapeutic vaccination, xenotransplantation, and certain biologic-device...

2013-11-25

142

Gene replacement therapy for retinal CNG channelopathies.  

PubMed

Visual phototransduction relies on the function of cyclic nucleotide-gated channels in the rod and cone photoreceptor outer segment plasma membranes. The role of these ion channels is to translate light-triggered changes in the second messenger cyclic guanosine 3'-5'-monophosphate levels into an electrical signal that is further processed within the retinal network and then sent to higher visual centers. Rod and cone photoreceptors express distinct CNG channels. The rod photoreceptor CNG channel is composed of one CNGB1 and three CNGA1 subunits, whereas the cone channel is formed by one CNGB3 and three CNGA3 subunits. Mutations in any of these channel subunits result in severe and currently untreatable retinal degenerative diseases like retinitis pigmentosa or achromatopsia. In this review, we provide an overview of the human diseases and relevant animal models of CNG channelopathies. Furthermore, we summarize recent results from preclinical gene therapy studies using adeno-associated viral vectors and discuss the efficacy and translational potential of these gene therapeutic approaches. PMID:23861024

Schön, Christian; Biel, Martin; Michalakis, Stylianos

2013-10-01

143

Imaging Cell Therapy for Myocardial Regeneration.  

PubMed

Noninvasive or minimally invasive imaging techniques are essential for developing strategies and assessing outcomes of cell-based therapies for myocardial regeneration, also referred to as cellular cardiomyoplasty. Imaging-based monitoring of cell survival is useful for selection of optimal cell type and evaluating strategies to enhance engraftment. Imaging-derived surrogate end points including global and regional contractile function, myocardial blood flow, or perfusion and bioenergetics have been used in clinical trials or in relevant large animal models to evaluate the therapeutic effect and mechanisms of action of cellular cardiomyoplasty. New techniques are emerging to assess electrical integration of donor cells with host cardiomyocytes. This review will summarize and highlight important and informative findings revealed by imaging in clinical and preclinical cellular cardiomyoplasty studies over the past 3 years. PMID:22905280

Zhang, Hualei; Qiao, Hui; Ferrari, Victor A; Zhou, Rong

2012-02-01

144

Gene Therapy for the Inner Ear: Challenges and Promises  

PubMed Central

Since the recognition of genes as the discrete units of heritability, and of DNA as their molecular substrate, the utilization of genes for therapeutic purposes has been recognized as a potential means of correcting genetic disorders. The tools of molecular biology, which allow the manipulation of DNA sequence, provided the means to put this concept into practice. However, progress in the implementation of these ideas has been slow. Here we review the history of the idea of gene therapy and the complexity of genetic disorders. We also discuss the requirements for sequence-based therapy to be accomplished for different types of inherited diseases, as well as the methods available for gene manipulation. The challenges that have limited the applications of gene therapy are reviewed, as are ethical concerns. Finally, we discuss the promise of gene therapy to address inherited and acquired disorders of the inner ear. PMID:19494569

Ryan, Allen F.; Dazert, Stefan

2015-01-01

145

Site-specific gene therapy for cardiovascular disease  

PubMed Central

Gene therapy holds considerable promise for the treatment of cardiovascular disease and may provide novel therapeutic solutions for both genetic disorders and acquired pathophysiologies such as arteriosclerosis, heart failure and arrhythmias. Recombinant DNA technology and the sequencing of the human genome have made a plethora of candidate therapeutic genes available for cardiovascular diseases. However, progress in the field of gene therapy for cardiovascular disease has been modest; one of the key reasons for this limited progress is the lack of gene delivery systems for localizing gene therapy to specific sites to optimize transgene expression and efficacy. This review summarizes progress made toward the site-specific delivery of cardiovascular gene therapy and highlights selected promising novel approaches. PMID:20205054

Fishbein, Ilia; Chorny, Michael; Levy, Robert J

2010-01-01

146

Image-guided radiation therapy: Physician's perspectives.  

PubMed

The evolution of radiotherapy has been ontogenetically linked to medical imaging. Over the years, major technological innovations have resulted in substantial improvements in radiotherapy planning, delivery, and verification. The increasing use of computed tomography imaging for target volume delineation coupled with availability of computer-controlled treatment planning and delivery systems have progressively led to conformation of radiation dose to the target tissues while sparing surrounding normal tissues. Recent advances in imaging technology coupled with improved treatment delivery allow near-simultaneous soft-tissue localization of tumor and repositioning of patient. The integration of various imaging modalities within the treatment room for guiding radiation delivery has vastly improved the management of geometric uncertainties in contemporary radiotherapy practice ushering in the paradigm of image-guided radiation therapy (IGRT). Image-guidance should be considered a necessary and natural corollary to high-precision radiotherapy that was long overdue. Image-guided radiation therapy not only provides accurate information on patient and tumor position on a quantitative scale, it also gives an opportunity to verify consistency of planned and actual treatment geometry including adaptation to daily variations resulting in improved dose delivery. The two main concerns with IGRT are resource-intensive nature of delivery and increasing dose from additional imaging. However, increasing the precision and accuracy of radiation delivery through IGRT is likely to reduce toxicity with potential for dose escalation and improved tumor control resulting in favourable therapeutic index. The radiation oncology community needs to leverage this technology to generate high-quality evidence to support widespread adoption of IGRT in contemporary radiotherapy practice. PMID:23293448

Gupta, T; Narayan, C Anand

2012-10-01

147

75 FR 66381 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...FDA-2010-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of...Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General...Retroviral and Lentiviral Vector Based Gene Therapy Products. FDA intends to...

2010-10-28

148

76 FR 9028 - Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products; Availability  

Federal Register 2010, 2011, 2012, 2013

...Industry: Potency Tests for Cellular and Gene Therapy Products; Availability AGENCY...Industry: Potency Tests for Cellular and Gene Therapy Products'' dated January 2011...provides manufacturers of cellular and gene therapy (CGT) products with...

2011-02-16

149

78 FR 44133 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...FDA-2013-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of...Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General...from the Office of Cellular, Tissue and Gene Therapies, Center for Biologics...

2013-07-23

150

76 FR 22405 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...FDA-2011-N-0002] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of...Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General...the committee will discuss cellular and gene therapy products for the treatment of...

2011-04-21

151

77 FR 65693 - Cellular, Tissue and Gene Therapies Advisory Committee; Amendment of Notice  

Federal Register 2010, 2011, 2012, 2013

...FDA-2012-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Amendment...a meeting of the Cellular, Tissue and Gene Therapies Advisory Committee. This meeting...a meeting of the Cellular, Tissue and Gene Therapies Advisory Committee would be...

2012-10-30

152

76 FR 81513 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...FDA-2011-N-0002] Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of...of Committee: Cellular, Tissue, and Gene Therapies Advisory Committee. General...Branch, Office of Cellular, Tissue and Gene Therapies, Center for Biologics...

2011-12-28

153

78 FR 79699 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...FDA-2013-N-0001] Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of...of Committee: Cellular, Tissue, and Gene Therapies Advisory Committee. General...from the Office of Cellular, Tissue, and Gene Therapies, Center for Biologics...

2013-12-31

154

75 FR 65640 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...FDA-2010-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of...Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General...Branch, Office of Cellular, Tissue and Gene Therapies, Center for Biologics...

2010-10-26

155

Gene and cell therapy for children — New medicines, new challenges??  

PubMed Central

The range of possible gene and cell therapy applications is expanding at an extremely rapid rate and advanced therapy medicinal products (ATMPs) are currently the hottest topic in novel medicines, particularly for inherited diseases. Paediatric patients stand to gain enormously from these novel therapies as it now seems plausible to develop a gene or cell therapy for a vast number of inherited diseases. There are a wide variety of potential gene and cell therapies in various stages of development. Patients who received first gene therapy treatments for primary immune deficiencies (PIDs) are reaching 10 and 15 years post-treatment, with robust and sustained immune recovery. Cell therapy clinical trials are underway for a variety of tissues including corneal, retinal and muscle repair and islet cell transplantation. Various cell therapy approaches are also being trialled to enhance the safety of bone marrow transplants, which should improve survival rates in childhood cancers and PIDs. Progress in genetic engineering of lymphocyte populations to target and kill cancerous cells is also described. If successful these ATMPs may enhance or replace the existing chemo-ablative therapy for several paediatric cancers. Emerging applications of gene therapy now include skin and neurological disorders such as epidermolysis bullosa, epilepsy and leukodystrophy. Gene therapy trials for haemophilia, muscular dystrophy and a range of metabolic disorders are underway. There is a vast array of potential advanced therapy medicinal products (ATMPs), and these are likely to be more cost effective than existing medicines. However, the first clinical trials have not been without setbacks and some of the key adverse events are discussed. Furthermore, the arrival of this novel class of therapies brings many new challenges for the healthcare industry. We present a summary of the key non-clinical factors required for successful delivery of these potential treatments. Technological advances are needed in vector design, raw material manufacture, cell culture and transduction methodology, and particularly in making all these technologies readily scalable. PMID:24583376

Buckland, Karen F.; Bobby Gaspar, H.

2014-01-01

156

Interactive Fly: Early Zygotic Gene Expression Images  

NSDL National Science Digital Library

In situ images from an award-winning and comprehensive site, The Interactive Fly. Entering through an expression pattern, this site thoroughly discusses each genes and shows its expression relative to other genes at this stage.

PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

2006-12-12

157

Methioninase cancer gene therapy with selenomethionine as suicide prodrug substrate.  

PubMed

In this study, we report a novel approach to gene-directed enzyme prodrug therapy for cancer. This gene therapy strategy exploits the toxic pro-oxidant property of methylselenol, which is released from selenomethionine (SeMET) by cancer cells with the adenoviral-delivered methionine alpha,gamma-lyase (MET) gene cloned from Pseudomonas putida. In MET-transduced tumor cells, the cytotoxicity of SeMET is increased up to 1000-fold compared with nontransduced cells. A strong bystander effect occurred because of methylselenol release from MET gene-transduced cells and uptake by surrounding tumor cells. Methylselenol damaged the mitochondria via oxidative stress and caused cytochrome c release into the cytosol, thereby activating the caspase cascade and apoptosis. Adenoviral MET-gene/SeMET treatment also inhibited tumor growth in rodents and significantly prolonged their survival. Recombinant adenovirus-encoding MET gene-SeMET treatment thereby offers a new paradigm for cancer gene therapy. PMID:11559554

Miki, K; Xu, M; Gupta, A; Ba, Y; Tan, Y; Al-Refaie, W; Bouvet, M; Makuuchi, M; Moossa, A R; Hoffman, R M

2001-09-15

158

Gene therapy strategies for hemophilia: benefits versus risks.  

PubMed

Hemophilia is an inherited bleeding disorder caused by a deficiency of functional clotting factors VIII or IX in the blood plasma. The drawbacks of the classical protein substitution therapy fueled interest in alternative treatments by gene therapy. Hemophilia has been recognized as an ideal target disease for gene therapy because a relatively modest increase in clotting factor levels can result in a significant therapeutic benefit. Consequently, introducing a functional FVIII or FIX gene copy into the appropriate target cells could ultimately provide a cure for hemophilic patients. Several cell types have been explored for hemophilia gene therapy, including hepatocytes, muscle, endothelial and hematopoietic cells. Both nonviral and viral vectors have been considered for the development of hemophilia gene therapy, including transposons, ?-retroviral, lentiviral, adenoviral and adeno-associated viral vectors. Several of these strategies have resulted in stable correction of the bleeding diathesis in hemophilia A and B murine as well as canine models, paving the way towards clinical trials. Although clotting factor expression has been detected in hemophilic patients treated by gene therapy, the challenge now lies in obtaining prolonged therapeutic FVIII or FIX levels in these patients. This review highlights the benefits and potential risks of the different gene therapy strategies for hemophilia that have been developed. PMID:20848668

Petrus, Inge; Chuah, Marinee; VandenDriessche, Thierry

2010-10-01

159

Despite the remarkable preclinical success of gene therapy, its clinical applications remain limited13  

E-print Network

Despite the remarkable preclinical success of gene therapy, its clinical applications remain gene therapy, the appropriate genes must be delivered to and expressed in target cells, without harming in 70% of gene therapy clinical trials as of January 2007 (REF. 5). Non- viral gene therapy, although

Cai, Long

160

Gene Therapy, Early Promises, Subsequent Problems, and Recent Breakthroughs  

PubMed Central

Gene therapy is one of the most attractive fields in medicine. The concept of gene delivery to tissues for clinical applications has been discussed around half a century, but scientist’s ability to manipulate genetic material via recombinant DNA technology made this purpose to reality. Various approaches, such as viral and non-viral vectors and physical methods, have been developed to make gene delivery safer and more efficient. While gene therapy initially conceived as a way to treat life-threatening disorders (inborn errors, cancers) refractory to conventional treatment, to date gene therapy is considered for many non–life-threatening conditions including those adversely influence on a patient’s quality of life. Gene therapy has made significant progress, including tangible success, although much slower than was initially predicted. Although, gene therapies still at a fairly primitive stage, it is firmly science based. There is justifiable hope that with enhanced pathobiological understanding and biotechnological improvements, gene therapy will be a standard part of clinical practice within 20 years. PMID:24312844

Razi Soofiyani, Saeideh; Baradaran, Behzad; Lotfipour, Farzaneh; Kazemi, Tohid; Mohammadnejad, Leila

2013-01-01

161

Advancements in gene transfer-based therapy for hemophilia A.  

PubMed

Gene therapy has promised clinical benefit to those suffering with hemophilia A, but this benefit has not yet been realized. However, during the past two decades, basic and applied gene therapy research has progressed and the goal of gene therapy for hemophilia A is once again in our sights. The hemophilia A patient population suffers from a disease that requires invasive, lifelong management, is exorbitantly expensive to treat, has geographically limited treatment access and can become untreatable due to immune reactions to the treatment product. Subsequent to the cloning of the factor VIII gene and cDNA in the early 1980s, academic and commercial research laboratories began to pursue gene transfer-based therapies to supplement or supplant the available protein replacement therapy. However, to date, clinical trials for gene therapy of hemophilia A have been unsuccessful. Three trials have been conducted with each having tested a different gene-transfer strategy and each demonstrating that there is a considerable barrier to achieving sustained expression of therapeutic amounts of factor VIII. Recent progress has been made in gene-transfer technology and, relevant to hemophilia A, towards increasing the biosynthetic efficiency of factor VIII. These advances are now being combined to develop novel strategies to treat and possibly cure hemophilia A. PMID:20577574

Doering, Christopher B; Spencer, H Trent

2009-12-01

162

Communicating in context: a priority for gene therapy researchers.  

PubMed

History shows that public opinion of emerging biotechnologies has the potential to impact the research process through mechanisms such as funding and advocacy. It is critical, therefore, to consider public attitudes towards modern biotechnology such as gene therapy and more specifically towards the ethics of gene therapy, alongside advances in basic and clinical research. Research conducted through social media recently assessed how online users view the ethics of gene therapy and showed that while acceptability is high, significant ethical concerns remain. To address these concerns, the development of effective and evidence-based communication strategies that engage a wide range of stakeholders should be a priority for researchers. PMID:25556839

Robillard, Julie M

2015-03-01

163

Nanoparticle PEGylation for imaging and therapy  

PubMed Central

Nanoparticles are an essential component in the emerging field of nanomedical imaging and therapy. When deployed in vivo, these materials are typically protected from the immune system by polyethylene glycol (PEG). A wide variety of strategies to coat and characterize nanoparticles with PEG has established important trends on PEG size, shape, density, loading level, molecular weight, charge and purification. Strategies to incorporate targeting ligands are also prevalent. This article presents a background to investigators new to stealth nanoparticles, and suggests some key considerations needed prior to designing a nanoparticle PEGylation protocol and characterizing the performance features of the product. PMID:21718180

Jokerst, Jesse V; Lobovkina, Tatsiana; Zare, Richard N; Gambhir, Sanjiv S

2011-01-01

164

Genetic correction using engineered nucleases for gene therapy applications.  

PubMed

Genetic mutations in humans are associated with congenital disorders and phenotypic traits. Gene therapy holds the promise to cure such genetic disorders, although it has suffered from several technical limitations for decades. Recent progress in gene editing technology using tailor-made nucleases, such as meganucleases (MNs), zinc finger nucleases (ZFNs), TAL effector nucleases (TALENs) and, more recently, CRISPR/Cas9, has significantly broadened our ability to precisely modify target sites in the human genome. In this review, we summarize recent progress in gene correction approaches of the human genome, with a particular emphasis on the clinical applications of gene therapy. PMID:24329887

Li, Hongmei Lisa; Nakano, Takao; Hotta, Akitsu

2014-01-01

165

Bacteriophage-Derived Vectors for Targeted Cancer Gene Therapy  

PubMed Central

Cancer gene therapy expanded and reached its pinnacle in research in the last decade. Both viral and non-viral vectors have entered clinical trials, and significant successes have been achieved. However, a systemic administration of a vector, illustrating safe, efficient, and targeted gene delivery to solid tumors has proven to be a major challenge. In this review, we summarize the current progress and challenges in the targeted gene therapy of cancer. Moreover, we highlight the recent developments of bacteriophage-derived vectors and their contributions in targeting cancer with therapeutic genes following systemic administration. PMID:25606974

Pranjol, Md Zahidul Islam; Hajitou, Amin

2015-01-01

166

The use of genes for performance enhancement: doping or therapy?  

PubMed

Recent biotechnological advances have permitted the manipulation of genetic sequences to treat several diseases in a process called gene therapy. However, the advance of gene therapy has opened the door to the possibility of using genetic manipulation (GM) to enhance athletic performance. In such 'gene doping', exogenous genetic sequences are inserted into a specific tissue, altering cellular gene activity or leading to the expression of a protein product. The exogenous genes most likely to be utilized for gene doping include erythropoietin (EPO), vascular endothelial growth factor (VEGF), insulin-like growth factor type 1 (IGF-1), myostatin antagonists, and endorphin. However, many other genes could also be used, such as those involved in glucose metabolic pathways. Because gene doping would be very difficult to detect, it is inherently very attractive for those involved in sports who are prepared to cheat. Moreover, the field of gene therapy is constantly and rapidly progressing, and this is likely to generate many new possibilities for gene doping. Thus, as part of the general fight against all forms of doping, it will be necessary to develop and continually improve means of detecting exogenous gene sequences (or their products) in athletes. Nevertheless, some bioethicists have argued for a liberal approach to gene doping. PMID:22030863

Oliveira, R S; Collares, T F; Smith, K R; Collares, T V; Seixas, F K

2011-12-01

167

Cerenkov Luminescence Imaging (CLI) for Cancer Therapy Monitoring  

PubMed Central

In molecular imaging, positron emission tomography (PET) and optical imaging (OI) are two of the most important and thus most widely used modalities1-3. PET is characterized by its excellent sensitivity and quantification ability while OI is notable for non-radiation, relative low cost, short scanning time, high throughput, and wide availability to basic researchers. However, both modalities have their shortcomings as well. PET suffers from poor spatial resolution and high cost, while OI is mostly limited to preclinical applications because of its limited tissue penetration along with prominent scattering optical signals through the thickness of living tissues. Recently a bridge between PET and OI has emerged with the discovery of Cerenkov Luminescence Imaging (CLI)4-6. CLI is a new imaging modality that harnesses Cerenkov Radiation (CR) to image radionuclides with OI instruments. Russian Nobel laureate Alekseyevich Cerenkov and his colleagues originally discovered CR in 1934. It is a form of electromagnetic radiation emitted when a charged particle travels at a superluminal speed in a dielectric medium7,8. The charged particle, whether positron or electron, perturbs the electromagnetic field of the medium by displacing the electrons in its atoms. After passing of the disruption photons are emitted as the displaced electrons return to the ground state. For instance, one 18F decay was estimated to produce an average of 3 photons in water5. Since its emergence, CLI has been investigated for its use in a variety of preclinical applications including in vivo tumor imaging, reporter gene imaging, radiotracer development, multimodality imaging, among others4,5,9,10,11. The most important reason why CLI has enjoyed much success so far is that this new technology takes advantage of the low cost and wide availability of OI to image radionuclides, which used to be imaged only by more expensive and less available nuclear imaging modalities such as PET. Here, we present the method of using CLI to monitor cancer drug therapy. Our group has recently investigated this new application and validated its feasibility by a proof-of-concept study12. We demonstrated that CLI and PET exhibited excellent correlations across different tumor xenografts and imaging probes. This is consistent with the overarching principle of CR that CLI essentially visualizes the same radionuclides as PET. We selected Bevacizumab (Avastin; Genentech/Roche) as our therapeutic agent because it is a well-known angiogenesis inhibitor13,14. Maturation of this technology in the near future can be envisioned to have a significant impact on preclinical drug development, screening, as well as therapy monitoring of patients receiving treatments. PMID:23183774

Xu, Yingding; Liu, Hongguang; Chang, Edwin; Jiang, Han; Cheng, Zhen

2012-01-01

168

Cerenkov Luminescence Imaging (CLI) for cancer therapy monitoring.  

PubMed

In molecular imaging, positron emission tomography (PET) and optical imaging (OI) are two of the most important and thus most widely used modalities. PET is characterized by its excellent sensitivity and quantification ability while OI is notable for non-radiation, relative low cost, short scanning time, high throughput, and wide availability to basic researchers. However, both modalities have their shortcomings as well. PET suffers from poor spatial resolution and high cost, while OI is mostly limited to preclinical applications because of its limited tissue penetration along with prominent scattering optical signals through the thickness of living tissues. Recently a bridge between PET and OI has emerged with the discovery of Cerenkov Luminescence Imaging (CLI). CLI is a new imaging modality that harnesses Cerenkov Radiation (CR) to image radionuclides with OI instruments. Russian Nobel laureate Alekseyevich Cerenkov and his colleagues originally discovered CR in 1934. It is a form of electromagnetic radiation emitted when a charged particle travels at a superluminal speed in a dielectric medium. The charged particle, whether positron or electron, perturbs the electromagnetic field of the medium by displacing the electrons in its atoms. After passing of the disruption photons are emitted as the displaced electrons return to the ground state. For instance, one (18)F decay was estimated to produce an average of 3 photons in water. Since its emergence, CLI has been investigated for its use in a variety of preclinical applications including in vivo tumor imaging, reporter gene imaging, radiotracer development, multimodality imaging, among others. The most important reason why CLI has enjoyed much success so far is that this new technology takes advantage of the low cost and wide availability of OI to image radionuclides, which used to be imaged only by more expensive and less available nuclear imaging modalities such as PET. Here, we present the method of using CLI to monitor cancer drug therapy. Our group has recently investigated this new application and validated its feasibility by a proof-of-concept study. We demonstrated that CLI and PET exhibited excellent correlations across different tumor xenografts and imaging probes. This is consistent with the overarching principle of CR that CLI essentially visualizes the same radionuclides as PET. We selected Bevacizumab (Avastin; Genentech/Roche) as our therapeutic agent because it is a well-known angiogenesis inhibitor. Maturation of this technology in the near future can be envisioned to have a significant impact on preclinical drug development, screening, as well as therapy monitoring of patients receiving treatments. PMID:23183774

Xu, Yingding; Liu, Hongguang; Chang, Edwin; Jiang, Han; Cheng, Zhen

2012-01-01

169

Percutaneous gene therapy heals cranial defects.  

PubMed

Nonhealing bone defects are difficult to treat. As the bone morphogenic protein and transforming growth factor beta pathways have been implicated in bone healing, we hypothesized that percutaneous Smad7 silencing would enhance signaling through both pathways and improve bone formation. Critical sized parietal trephine defects were created and animals received percutaneous injection of: agarose alone or agarose containing nonsense or Smad7 small interfering RNA (siRNA). At 12 weeks, SMADs1, 2, 3, 5, 7 and 8 levels were assessed. Smad1/5/8 osteogenic target, Dlx5, and SMAD2/3 angiogenic target, plasminogen activator inhibitor-1 (Pai1), transcription levels were measured. Noncanonical signaling through TGF? activated kinase-1 (Tak1) and target, runt-related transcription factor 2 (Runx2) and collagen1?1 (Col1?1), transcription were also measured. Micro-computed tomography and Gomori trichome staining were used to assess healing. Percutaneous injection of Smad7 siRNA significantly knocked down Smad7 mRNA (86.3 ± 2.5%) and protein levels (46.3 ± 3.1%). The SMAD7 knockdown resulted in a significant increase in receptor-regulated SMADs (R-SMAD) (Smad 1/5/8 and Smad2/3) nuclear translocation. R-SMAD nuclear translocation increased Dlx5 and Pai1 transcription. Additionally, noncanonical signaling through Tak1 increased Runx2 and Col1?1 target transcription. Compared with animals treated with agarose alone (33.9 ± 2.8% healing) and nonsense siRNA (31.5 ± 11.8% healing), animals treated Smad7 siRNA had significantly great (91.2 ± 3.8%) healing. Percutaneous Smad7 silencing increases signal transduction through canonical and noncanonical pathways resulting in significant bone formation. Minimally invasive gene therapies may prove effective in the treatment of nonhealing bone defects. PMID:23594990

Layliev, J; Sagebin, F; Weinstein, A; Marchac, A; Szpalski, C; Saadeh, P B; Warren, S M

2013-09-01

170

Noncoding oligonucleotides: the belle of the ball in gene therapy.  

PubMed

Gene therapy carries the promise of cures for many diseases based on manipulating the expression of a person's genes toward the therapeutic goal. The relevance of noncoding oligonucleotides to human disease is attracting widespread attention. Noncoding oligonucleotides are not only involved in gene regulation, but can also be modified into therapeutic tools. There are many strategies that leverage noncoding oligonucleotides for gene therapy, including small interfering RNAs, antisense oligonucleotides, aptamers, ribozymes, decoys, and bacteriophage phi 29 RNAs. In this chapter, we will provide a broad, comprehensive overview of gene therapies that use noncoding oligonucleotides for disease treatment. The mechanism and development of each therapeutic will be described, with a particular focus on its clinical development. Finally, we will discuss the challenges associated with developing nucleic acid therapeutics and the prospects for future success. PMID:25620011

Shum, Ka-To; Rossi, John J

2015-01-01

171

Imaging of enzyme replacement therapy using PET  

PubMed Central

Direct enzyme replacement therapy (ERT) has been introduced as a means to treat a number of rare, complex genetic conditions associated with lysosomal dysfunction. Gaucher disease was the first for which this therapy was applied and remains the prototypical example. Although ERT using recombinant lysosomal enzymes has been shown to be effective in altering the clinical course of Gaucher disease, Fabry disease, Hurler syndrome, Hunter syndrome, Maroteaux-Lamy syndrome, and Pompe disease, the recalcitrance of certain disease manifestations underscores important unanswered questions related to dosing regimes, tissue half-life of the recombinant enzyme and the ability of intravenously administered enzyme to reach critical sites of known disease pathology. We have developed an innovative method for tagging acid ?-glucocerebrosidase (GCase), the recombinant enzyme formulated in Cerezyme® used to treat Gaucher disease, using an 18F-labeled substrate analogue that becomes trapped within the active site of the enzyme. Using micro-PET we show that the tissue distribution of injected enzyme can be imaged in a murine model and that the PET data correlate with tissue 18F counts. Further we show that PET imaging readily monitors pharmacokinetic changes effected by receptor blocking. The ability to 18F-label GCase to monitor the enzyme distribution and tissue half-life in vivo by PET provides a powerful research tool with an immediate clinical application to Gaucher disease and a clear path for application to other ERTs. PMID:20534487

Phenix, Christopher P.; Rempel, Brian P.; Colobong, Karen; Doudet, Doris J.; Adam, Michael J.; Clarke, Lorne A.; Withers, Stephen G.

2010-01-01

172

363. Gene Delivery to Human Sweat Glands: A Model for Cystic Fibrosis Gene Therapy  

Microsoft Academic Search

Cystic fibrosis (CF) is considered a disease that could be treated by gene therapy, yet the results from past clinical trials showed only transient transgene expression. Gene therapy vectors are mostly studied in cultured cells, rodent models or non-human primates, but it is difficult to test them in human system prior to clinical studies. In this study, we investigated the

Haeyul Lee; David R. Koehler; Cho Y. Pang; Ronald H. Levine; Philip Ng; Donna J. Palmer; Paul M. Quinton; Jim Hu

2005-01-01

173

GENE THERAPY FOR ORAL CANCER- JOURNEY TO A NEW HORIZON  

E-print Network

The past two decades have been golden years for the genetics of cancer. It has become clear through the work of countless laboratory groups that both inherited and sporadic cancers arise through defects or misregulations of their genomes. Despite advances in surgery, radiotherapy, and chemotherapy, the survival of patients with oral squamous cell carcinoma have not significantly improved over the past several decades. Thus, an entirely new approach to its treatment utilizing genetic aids has evolved. The majority of the head and neck cancers comprise of Oral squamous cell carcinoma (OSCC). The traditional therapies for the management of cancer and their various modifications including surgery, radiotherapy and chemotherapy have not refined the survival rates yet. Gene therapy represents a fundamentally new mode for the effective treatment of a disease. It essentially consists of the introduction of the genetic material into the target cells of an individual without producing toxic effects on surrounding tissues. The essence of gene therapy is attributed to the replacement of the defective gene with a normal gene, thus restoring the lost function in the patient's body. The aim of this review is to analyze the different modalities of gene therapy currently used to manage precancerous and cancerous lesions of the oral cavity. Key words: Gene, Gene therapy, Oral squamous cell carcinoma, Vectors

Arun Singh; Manjunath Badni; Anil Singh; Fahad M Samadi; Arpita Kabiraj

174

Abstract. Gene therapy is an exciting novel approach for treating cancers resistant to currently available modalities.  

E-print Network

Abstract. Gene therapy is an exciting novel approach for treating cancers resistant to currently of previous strategies. Adenoviral cancer gene therapy approaches lack cross-resistance with other treatment. Cancer gene therapy approaches 4. Adenovirus for gene therapy 5. Cancer trials with adenoviral vectors 6

Hemminki, Akseli

175

Laboratory Investigation Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy  

E-print Network

Laboratory Investigation Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy, Switzerland Key words: 9L gliosarcoma, advanced brain tumor, gene-mediated immunoprophylaxis, microbeam radiation therapy, rats Summary Purpose: Microbeam radiation therapy (MRT), a novel experimental

Terasaki, Mark

176

Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy  

E-print Network

Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy Timothy K. Lua, we engineered bacteriophage to overexpress proteins and attack gene networks that are not directly bacteriophage en- hances killing by quinolones by several orders of magnitude in vitro and significantly

Collins, James J.

177

Photoacoustic imaging and temperature measurement for photothermal cancer therapy  

PubMed Central

Photothermal therapy is a noninvasive, targeted, laser-based technique for cancer treatment. During photothermal therapy, light energy is converted to heat by tumor-specific photoabsorbers. The corresponding temperature rise causes localized cancer destruction. For effective treatment, however, the presence of photoabsorbers in the tumor must be ascertained before therapy and thermal imaging must be performed during therapy. This study investigates the feasibility of guiding photothermal therapy by using photoacoustic imaging to detect photoabsorbers and to monitor temperature elevation. Photothermal therapy is carried out by utilizing a continuous wave laser and metal nanocomposites broadly absorbing in the near-infrared optical range. A linear array-based ultrasound imaging system is interfaced with a nanosecond pulsed laser to image tissue-mimicking phantoms and ex-vivo animal tissue before and during photothermal therapy. Before commencing therapy, photoacoustic imaging identifies the presence and spatial location of nanoparticles. Thermal maps are computed by monitoring temperature-induced changes in the photoacoustic signal during the therapeutic procedure and are compared with temperature estimates obtained from ultrasound imaging. The results of our study suggest that photoacoustic imaging, augmented by ultrasound imaging, is a viable candidate to guide photoabsorber-enhanced photothermal therapy. PMID:18601569

Shah, Jignesh; Park, Suhyun; Aglyamov, Salavat; Larson, Timothy; Ma, Li; Sokolov, Konstantin; Johnston, Keith; Milner, Thomas; Emelianov, Stanislav Y.

2009-01-01

178

review The American Society of Gene & Cell Therapy Molecular Therapy vol. 19 no. 8, 14071415 aug. 2011 1407  

E-print Network

review© The American Society of Gene & Cell Therapy Molecular Therapy vol. 19 no. 8, 1407­1415 aug. 2011 1407 IntroductIon Gene therapy has shown increasing promise in clinical trials for disorders in the development of gene delivery systems must continue to build upon the recent successes in the field and further

Schaffer, David V.

179

14 2 GENE THERAPY IN ORAL SQUAMOUS CELL CARCINOMA-  

E-print Network

Oral cancer remains one of the leading causes of death world wide. Various means to destroy tumor cells preferentially have been developed; gene therapy is one among them with less treatment morbidity. Gene therapy involves the transfer of therapeutic or working copy of genes into a specific cell of an individual in order to repair a faulty copy of gene. The alteration can be accomplished by repairing or replacing the damaged DNA by various strategies and vectors. To date genetically altered viruses are commonly used as gene delivery vehicle (vector) which has an advantage of evolutionary selection of host-virus relation. Non viral vectors which include the physical transfection of genes can be accomplished by electrophoration, microinjection, or use of ballistic particles and chemical transfection by forming liposomes.

A Short Review; P. M. Sunil; Isaac Joseph; Soma Susan Varghese

180

Objective Assessment of Image Quality VI: Imaging in Radiation Therapy  

PubMed Central

Earlier work on Objective Assessment of Image Quality (OAIQ) focused largely on estimation or classification tasks in which the desired outcome of imaging is accurate diagnosis. This paper develops a general framework for assessing imaging quality on the basis of therapeutic outcomes rather than diagnostic performance. By analogy to Receiver Operating Characteristic (ROC) curves and their variants as used in diagnostic OAIQ, the method proposed here utilizes the Therapy Operating Characteristic or TOC curves, which are plots of the probability of tumor control vs. the probability of normal-tissue complications as the overall dose level of a radiotherapy treatment is varied. The proposed figure of merit is the area under the TOC curve, denoted AUTOC. This paper reviews an earlier exposition of the theory of TOC and AUTOC, which was specific to the assessment of image-segmentation algorithms, and extends it to other applications of imaging in external-beam radiation treatment as well as in treatment with internal radioactive sources. For each application, a methodology for computing the TOC is presented. A key difference between ROC and TOC is that the latter can be defined for a single patient rather than a population of patients. PMID:24200954

Barrett, Harrison H.; Kupinski, Matthew A.; Müeller, Stefan; Halpern, Howard J.; Morris, John C.; Dwyer, Roisin

2015-01-01

181

Objective assessment of image quality VI: imaging in radiation therapy  

NASA Astrophysics Data System (ADS)

Earlier work on objective assessment of image quality (OAIQ) focused largely on estimation or classification tasks in which the desired outcome of imaging is accurate diagnosis. This paper develops a general framework for assessing imaging quality on the basis of therapeutic outcomes rather than diagnostic performance. By analogy to receiver operating characteristic (ROC) curves and their variants as used in diagnostic OAIQ, the method proposed here utilizes the therapy operating characteristic or TOC curves, which are plots of the probability of tumor control versus the probability of normal-tissue complications as the overall dose level of a radiotherapy treatment is varied. The proposed figure of merit is the area under the TOC curve, denoted AUTOC. This paper reviews an earlier exposition of the theory of TOC and AUTOC, which was specific to the assessment of image-segmentation algorithms, and extends it to other applications of imaging in external-beam radiation treatment as well as in treatment with internal radioactive sources. For each application, a methodology for computing the TOC is presented. A key difference between ROC and TOC is that the latter can be defined for a single patient rather than a population of patients.

Barrett, Harrison H.; Kupinski, Matthew A.; Müeller, Stefan; Halpern, Howard J.; Morris, John C., III; Dwyer, Roisin

2013-11-01

182

Gene therapy of primary T cell immunodeficiencies Alain Fischer 1,2,3  

E-print Network

1 Gene therapy of primary T cell immunodeficiencies Alain Fischer 1,2,3 Salima Hacein-Bey-Abina 1, published in "Gene 2013;13:361-2" DOI : 10.1016/j.gene.2013.03.092 #12;2 ABSTRACT Gene therapy of severe, will be thus very informative. Keywords: gene therapy; severe combined immune deficiencies; retrovirus

Paris-Sud XI, Université de

183

Adenovirus-Based p53 Gene Therapy in Ovarian Cancer  

Microsoft Academic Search

Mutations of the p53 tumor suppressor gene are the most common molecular genetic abnormality to be described in ovarian cancer. To determine the feasibility of mutant p53 as a molecular target for gene therapy in ovarian cancer, we constructed an adenovirus vector containing the wild-type p53 gene. The ability of this adenovirus construct (Ad–CMV–p53) to express p53 protein was examined

JOSEPH T. SANTOSO; DE-CHU TANG; JACLYN HUNG; DEBORAH J. REED; CAROLYN Y. MULLER; DAVID P. CARBONE; JOSEPH A. LUCCIIII; DAVID SCOTTMILLER; MICHAEL J. MATHIS

1995-01-01

184

Safety of gene therapy: new insights to a puzzling case.  

PubMed

Over the last few years, the transfer of therapeutic genes via gammaretro- or lentiviral vector systems has proven its virtue as an alternative treatment for a series of genetic disorders. The number of approved phase I/II clinical trials, especially for rare diseases, is steadily increasing, but the overall hurdles to become a broadly acceptable therapy remain numerous. The efforts by clinicians and basic scientists have tremendously improved the knowledge available about feasibility and biosafety of gene therapy. Nonetheless, despite the generation of a plethora of clinical and preclinical safety data, we still lack sufficiently powerful assays to predictively assess the exact levels of toxicity that might be observed in any given clinical gene therapy. Insertional mutagenesis is one of the major concerns when using integrating vectors for permanent cell modification, and the occurrence of adverse events related to genotoxicity, in early gene therapy trials, has refrained the field of gene therapy from emerging further. In this review, we provided a comprehensive overview on the basic principles and potential co-factors concurring in the generation of adverse events reported in gene therapy clinical trials using integrating vectors. Additionally, we summarized the available systems to assess genotoxicity at the preclinical level and we shed light on the issues affecting the predictive value of these assays when translating their results into the clinical arena. In the last section of the review we briefly touched on the future trends and how they could increase the safety of gene therapy employing integrating vector technology to take it to the next level. PMID:25245088

Rothe, Michael; Schambach, Axel; Biasco, Luca

2014-01-01

185

Gene therapy (germ line), Mario CapecchiSite: DNA Interactive (www.dnai.org)  

NSDL National Science Digital Library

Interviewee: Mario Capecchi DNAi Location: Applications>Genes and Medicine>Gene targeting>Possibilities Cell therapy (germline) Mario Capecchi discusses the idea that someday therapies may be created to correct defective genes in egg and sperm cells.

2008-03-26

186

77 FR 63840 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...FDA-2012-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of...Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General...hear updates of research programs in the Gene Transfer and Immunogenicity Branch,...

2012-10-17

187

Theranostic GO-based nanohybrid for tumor induced imaging and potential combinational tumor therapy.  

PubMed

Graphene oxide (GO)-based theranostic nanohybrid is designed for tumor induced imaging and potential combinational tumor therapy. The anti-tumor drug, Doxorubicin (DOX) is chemically conjugated to the poly(ethylenimine)-co-poly(ethylene glycol) (PEI-PEG) grafted GO via a MMP2-cleavable PLGLAG peptide linkage. The therapeutic efficacy of DOX is chemically locked and its intrinsic fluorescence is quenched by GO under normal physiological condition. Once stimulated by the MMP2 enzyme over-expressed in tumor tissues, the resulting peptide cleavage permits the unloading of DOX for tumor therapy and concurrent fluorescence recovery of DOX for in situ tumor cell imaging. Attractively, this PEI-bearing nanohybrid can mediate efficient DNA transfection and shows great potential for combinational drug/gene therapy. This tumor induced imaging and potential combinational therapy will open a window for tumor treatment by offering a unique theranostic approach through merging the diagnostic capability and pathology-responsive therapeutic function. PMID:24000121

Qin, Si-Yong; Feng, Jun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Liu, Xiang-Ji; Luo, Guo-Feng; Zhuo, Ren-Xi; Zhang, Xian-Zheng

2014-02-12

188

Gene therapy for the prevention of vein graft disease  

PubMed Central

Ischemic cardiovascular disease remains the leading cause of death worldwide. Despite advances in the medical management of atherosclerosis over the past several decades, many patients require arterial revascularization to reduce mortality and alleviate ischemic symptoms. Technological advancements have led to dramatic increases in the use of percutaneous and endovascular approaches, yet surgical revascularization (bypass surgery) with autologous vein grafts remains a mainstay of therapy for both coronary and peripheral artery disease. Although bypass surgery is highly efficacious in the short-term, long-term outcomes are limited by relatively high failure rates as a result of intimal hyperplasia, which is a common feature of vein graft disease. The supply of native veins is limited, and many individuals require multiple grafts and repeat procedures. The need to prevent vein graft failure has led to great interest in gene therapy approaches to this problem. Bypass grafting presents an ideal opportunity for gene therapy, as surgically harvested vein grafts can be treated with gene delivery vectors ex vivo, thereby maximizing gene delivery while minimizing the potential for systemic toxicity and targeting the pathogenesis of vein graft disease at its onset. Here we will review the pathogenesis of vein graft disease and discuss vector delivery strategies and potential molecular targets for its prevention. We will summarize the preclinical and clinical literature on gene therapy in vein grafting and discuss additional considerations for future therapies to prevent vein graft disease. PMID:23274305

Southerland, Kevin W.; Frazier, Sarah B.; Bowles, Dawn E.; Milano, Carmelo A.; Kontos, Christopher D.

2013-01-01

189

original article The American Society of Gene & Cell Therapy Molecular Therapy vol. 20 no. 2, 329338 feb. 2012 329  

E-print Network

original article© The American Society of Gene & Cell Therapy Molecular Therapy vol. 20 no. 2, 329 are of particular interest for their capacity to mediate efficient gene delivery to and gene targeting in various have applied this approach to create a novel AAV variant with high gene delivery efficiencies (~50

Schaffer, David V.

190

original article The American Society of Gene & Cell Therapy Molecular Therapy vol. 19 no. 4, 667675 apr. 2011 667  

E-print Network

original article© The American Society of Gene & Cell Therapy Molecular Therapy vol. 19 no. 4, 667­675 apr. 2011 667 Gene delivery to, and gene targeting in, stem cells would be a highly enabling- neering AAV delivery systems to enhance gene delivery to stem cells may have an impact in stem cell

Schaffer, David V.

191

Nitric oxide synthase gene therapy: progress and prospects.  

PubMed

NOS gene therapy has been the focus of extensive research as dysfunction of this enzyme has been implicated in several cardiovascular diseases. Research has concentrated on comparing the effect of gene delivery of NOS isoforms (eNOS, iNOS and nNOS) in healthy and diseased animal models on intimal hyperplasia, restenosis, vascular tone and ischemia-reperfusion injury. Most results demonstrate therapeutic benefits following vascular gene delivery of all NOS in pre-clinical models of cardiovascular disease. eNOS has been shown to have particular promise as it promotes re-endothelialisation and inhibits intimal hyperplasia in injured blood vessels. The ultimate goal is to translate the benefit of NOS gene therapy in animal models into clinical practise. To develop NOS gene therapy for clinical use further work needs to be undertaken to improve delivery systems and vectors to minimise detrimental side-effects and enhance positive treatment outcomes. This review focuses on current research on NOS gene therapy in cardiovascular disease and identifies the next steps that would be necessary to lead to clinical trials. PMID:19463074

O'Connor, Deirdre M; O'Brien, Timothy

2009-07-01

192

Retinal Structure and Function in Achromatopsia: Implications for Gene Therapy  

PubMed Central

Purpose To characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical trials of gene therapy. Design Cross-sectional study. Participants Forty subjects with ACHM. Methods All subjects underwent spectral domain optical coherence tomography (SD-OCT), microperimetry, and molecular genetic testing. Foveal structure on SD-OCT was graded into 5 distinct categories: (i) continuous inner segment ellipsoid (ISe), (ii) ISe disruption, (iii) ISe absence, (iv) presence of a hyporeflective zone (HRZ), and (v) outer retinal atrophy including retinal pigment epithelial (RPE) loss. Foveal and outer nuclear layer (ONL) thickness was measured, and presence of hypoplasia determined. Main Outcome Measures Photoreceptor appearance on SD-OCT imaging; foveal and ONL thickness; presence of foveal hypoplasia; retinal sensitivity and fixation stability; and association of these parameters with age and genotype. Results Forty subjects with mean age of 24.9 years (range 6 to 52) were included. Disease-causing variants were found in CNGA3 (n=18), CNGB3 (n=15), GNAT2 (n=4), and PDE6C (n=1). No variants were found in 2 individuals. 22.5% of subjects had a continuous ISe layer at the fovea; 27.5% had ISe disruption; 20% had an absent ISe layer; 22.5% had a HRZ; and 7.5% had outer retinal atrophy. No significant differences in age (p=0.77), mean retinal sensitivity (p=0.21) or fixation stability (p=0.34) across the 5 SD-OCT categories were evident. No significant correlation was found between age and foveal thickness (p=0.84), or between age and foveal ONL thickness (p=0.12). Conclusions The lack of clear association of disruption of retinal structure or function in ACHM with age suggests that the window of opportunity for intervention by gene therapy is wider in some individuals than previously indicated. Therefore the potential benefit for a given subject is likely to be better predicted by specific measurement of photoreceptor structure rather than simply by age. The ability to directly assess cone photoreceptor preservation with SD-OCT and/or adaptive optics imaging is likely to prove invaluable in selecting subjects for future trials and measuring their impact. PMID:24148654

Sundaram, Venki; Wilde, Caroline; Aboshiha, Jonathan; Cowing, Jill; Han, Colin; Langlo, Christopher S.; Chana, Ravinder; Davidson, Alice E.; Sergouniotis, Panagiotis I.; Bainbridge, James W.; Ali, Robin R.; Dubra, Alfredo; Rubin, Gary; Webster, Andrew R.; Moore, Anthony T.; Nardini, Marko; Carroll, Joseph; Michaelides, Michel

2013-01-01

193

Gene therapy for acute lung injury  

Microsoft Academic Search

The remarkable transition of biological science into the age of molecular biology held great promise for development of new therapies for treatment of human disease. The fact that the technology exists for analyzing genetic material in exquisite detail and constructing DNA in virtually any desired form was the basis for promising rapid translation into clinical medicine and the final cure

K. L. Brigham; A. A. Stecenko

2000-01-01

194

Breast cancer gene therapy: transgenic immunotherapy  

Microsoft Academic Search

A number of studies have demonstrated that potent anti-tumor immunity can be induced using cytokine gene transfer, a strategy termed transgenic immunotherapy. Our aim is to express cytokine genes in the vicinity of tumor cells, either by transducing tumor cells themselves, or by delivering cytokine-expressing endothelial cells to tumor sites. We compared the ability of cytokine-expressing tumor cells or endothelial

Ning Su; John O. Ojeifo; Alexander MacPherson; James A. Zwiebel

1994-01-01

195

Gene therapy, fundamental rights, and the mandates of public health.  

PubMed

Recent and near-future developments in the field of molecular biology will make possible the treatment of genetic disease on an unprecedented scale. The potential applications of these developments implicate important public policy considerations. Among the questions that may arise is the constitutionality of a state-mandated program of gene therapy for the purpose of eradicating certain genetic diseases. Though controversial, precedents of public health jurisprudence suggest that such a program could survive constitutional scrutiny. This article provides an overview of gene therapy in the context of fundamental rights and the mandates of public health. PMID:15255004

Lynch, John

2004-01-01

196

on and Gene Therapy Volume 7, Number 1, 2001THE NEUROSCIENTIST  

E-print Network

on and Gene Therapy Volume 7, Number 1, 2001THE NEUROSCIENTIST n REVIEW Transplantation and Gene genes to protect neurons and to stimulate regeneration. The ability to engineer cells by gene therapy Therapy: Combined Approaches for Repair of Spinal Cord Injury MARION MURRAY and ITZHAK FISCHER Department

Fischer, Itzhak

197

Capsid-Modified Adenoviral Vectors for Improved Muscle-Directed Gene Therapy  

E-print Network

Capsid-Modified Adenoviral Vectors for Improved Muscle-Directed Gene Therapy Kilian Guse,1 Masataka represents an attractive target tissue for adenoviral gene therapy to treat muscle disorders-directed gene therapy. Introduction Skeletal muscle-directed gene transfer holds promise for the treatment

Hemminki, Akseli

198

ORIGINAL ARTICLE Retroviral vector insertions in T-lymphocytes used for suicide gene therapy  

E-print Network

ORIGINAL ARTICLE Retroviral vector insertions in T-lymphocytes used for suicide gene therapy occur Keywords: GvHD; T-lymphocytes; suicide gene therapy; HSV-TK; ligation-mediated PCR; preferred integration retroviral gene marking study8 and in a clinical gene therapy trial for X-chromosomal severe combined

Granada, Universidad de

199

Biosafety challenges for use of lentiviral vectors in gene therapy.  

PubMed

Lentiviral vectors are promising tools for the genetic modification of cells in biomedical research and gene therapy. Their use in recent clinical trials for the treatment of adrenoleukodystrophy, ?-thalassemia, Wiskott-Aldrich- Syndrome and metachromatic leukodystrophy underlined their efficacy for therapies especially in case of hereditary diseases. In comparison to gammaretroviral LTR-driven vectors, which were employed in the first clinical trials, lentiviral vectors present with some favorable features like the ability to transduce also non-dividing cells and a potentially safer insertion profile. However, genetic modification with viral vectors in general and stable integration of the therapeutic gene into the host cell genome bear concerns with respect to different levels of personal or environmental safety. Among them, insertional mutagenesis by enhancer mediated dysregulation of neighboring genes or aberrant splicing is still the biggest concern. However, also risks like immunogenicity of vector particles, the phenotoxicity of the transgene and potential vertical or horizontal transmission by replication competent retroviruses need to be taken into account. This review will give an overview on biosafety aspects that are relevant to the use of lentiviral vectors for genetic modification and gene therapy. Furthermore, assay systems aiming at evaluating biosafety in preclinical settings and recent promising clinical trials including efforts of monitoring of patients after gene therapy will be discussed. PMID:24195603

Rothe, Michael; Modlich, Ute; Schambach, Axel

2013-12-01

200

Non-viral vectors for gene-based therapy.  

PubMed

Gene-based therapy is the intentional modulation of gene expression in specific cells to treat pathological conditions. This modulation is accomplished by introducing exogenous nucleic acids such as DNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA) or antisense oligonucleotides. Given the large size and the negative charge of these macromolecules, their delivery is typically mediated by carriers or vectors. In this Review, we introduce the biological barriers to gene delivery in vivo and discuss recent advances in material sciences, nanotechnology and nucleic acid chemistry that have yielded promising non-viral delivery systems, some of which are currently undergoing testing in clinical trials. The diversity of these systems highlights the recent progress of gene-based therapy using non-viral approaches. PMID:25022906

Yin, Hao; Kanasty, Rosemary L; Eltoukhy, Ahmed A; Vegas, Arturo J; Dorkin, J Robert; Anderson, Daniel G

2014-08-01

201

Glaucoma: genes, phenotypes, and new directions for therapy  

PubMed Central

Glaucoma, a leading cause of blindness worldwide, is characterized by progressive optic nerve damage, usually associated with intraocular pressure. Although the clinical progression of the disease is well defined, the molecular events responsible for glaucoma are currently poorly understood and current therapeutic strategies are not curative. This review summarizes the human genetics and genomic approaches that have shed light on the complex inheritance of glaucoma genes and the potential for gene-based and cellular therapies that this research makes possible. PMID:20811162

Fan, Bao Jian; Wiggs, Janey L.

2010-01-01

202

Neural Stem Cell-based Gene Therapy for Brain Tumors  

Microsoft Academic Search

Advances in gene-based medicine since 1990s have ushered in new therapeutic strategy of gene therapy for inborn error genetic\\u000a diseases and cancer. Malignant brain tumors such as glioblastoma multiforme and medulloblastoma remain virtually untreatable\\u000a and lethal. Currently available treatment for brain tumors including radical surgical resection followed by radiation and\\u000a chemotherapy, have substantially improved the survival rate in patients suffering

Seung U. Kim

2011-01-01

203

Molecular Imaging in Stem Cell Therapy for Spinal Cord Injury  

PubMed Central

Spinal cord injury (SCI) is a serious disease of the center nervous system (CNS). It is a devastating injury with sudden loss of motor, sensory, and autonomic function distal to the level of trauma and produces great personal and societal costs. Currently, there are no remarkable effective therapies for the treatment of SCI. Compared to traditional treatment methods, stem cell transplantation therapy holds potential for repair and functional plasticity after SCI. However, the mechanism of stem cell therapy for SCI remains largely unknown and obscure partly due to the lack of efficient stem cell trafficking methods. Molecular imaging technology including positron emission tomography (PET), magnetic resonance imaging (MRI), optical imaging (i.e., bioluminescence imaging (BLI)) gives the hope to complete the knowledge concerning basic stem cell biology survival, migration, differentiation, and integration in real time when transplanted into damaged spinal cord. In this paper, we mainly review the molecular imaging technology in stem cell therapy for SCI. PMID:24701583

Tian, Mei; Zhang, Hong

2014-01-01

204

Antisense Gene Silencing: Therapy for Neurodegenerative Disorders?  

PubMed Central

Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique. This review will focus on how RNAi has developed over the years and how the technique is exploited in a pre-clinical and clinical perspective in relation to neurodegenerative disorders. PMID:24705213

Nielsen, Troels T.; Nielsen, Jørgen E.

2013-01-01

205

Translational Applications of Molecular Imaging and Radionuclide Therapy  

SciTech Connect

Molecular imaging is becoming a larger part of imaging research and practice. The Office of Biological and Environmental Research of the Department of Energy funds a significant number of researchers in this area. The proposal is to partially fund a workshop to inform scientists working in nuclear medicine and nuclear medicine practitioners of the recent advances of molecular imaging in nuclear medicine as well as other imaging modalities. A limited number of topics related to radionuclide therapy will also be discussed. The proposal is to request partial funds for the workshop entitled “Translational Applications of Molecular Imaging and Radionuclide Therapy” to be held prior to the Society of Nuclear Medicine Annual Meeting in Toronto, Canada in June 2005. The meeting will be held on June 17-18. This will allow scientists interested in all aspects of nuclear medicine imaging to attend. The chair of the organizing group is Dr. Michael J. Welch. The organizing committee consists of Dr. Welch, Dr. William C. Eckelman and Dr. David Vera. The goal is to invite speakers to discuss the most recent advances of modern molecular imaging and therapy. Speakers will present advances made in in vivo tagging imaging assays, technical aspects of small animal imaging, in vivo imaging and bench to bedside translational study – the role of a diagnostic scan on therapy selection. This latter topic will include discussions on ? therapy and new approaches to dosimetry. Several of these topics are those funded by the Department of Energy Office of Biological and Environmental Research.

Welch, Michael J.; Eckelman, William C.; Vera, David

2005-06-17

206

Human Cone Visual Pigment Deletions Spare Sufficient Photoreceptors to Warrant Gene Therapy  

PubMed Central

Abstract Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5–58) with large deletions in the red/green opsin gene array. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed the existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM. PMID:24067079

Cideciyan, Artur V.; Hufnagel, Robert B.; Carroll, Joseph; Sumaroka, Alexander; Luo, Xunda; Schwartz, Sharon B.; Dubra, Alfredo; Land, Megan; Michaelides, Michel; Gardner, Jessica C.; Hardcastle, Alison J.; Moore, Anthony T.; Sisk, Robert A.; Ahmed, Zubair M.; Kohl, Susanne

2013-01-01

207

HSV Recombinant Vectors for Gene Therapy  

PubMed Central

The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), has allowed the development of potential replication-competent and replication-defective vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous systems, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases, and targeted infection to specific tissues or organs. Replication-defective recombinant vectors are non-toxic gene transfer tools that preserve most of the neurotropic features of wild type HSV-1, particularly the ability to express genes after having established latent infections, and are thus proficient candidates for therapeutic gene transfer settings in neurons. A replication-defective HSV vector for the treatment of pain has recently entered in phase 1 clinical trial. Replication-competent (oncolytic) vectors are becoming a suitable and powerful tool to eradicate brain tumours due to their ability to replicate and spread only within the tumour mass, and have reached phase II/III clinical trials in some cases. The progress in understanding the host immune response induced by the vector is also improving the use of HSV as a vaccine vector against both HSV infection and other pathogens. This review briefly summarizes the obstacle encountered in the delivery of HSV vectors and examines the various strategies developed or proposed to overcome such challenges. PMID:20835362

Manservigi, Roberto; Argnani, Rafaela; Marconi, Peggy

2010-01-01

208

Gene Therapy for Lysosomal Storage Diseases  

Microsoft Academic Search

Lysosomal storage diseases (LSDs) comprise a diverse group of monogenetic disorders with complex clinical phenotypes that include both systemic and central nervous system pathologies. In recent years, the identification or development of mouse models recapitulating the clinical course of the LSDs has been instrumental in evaluating therapeutic strategies. Here, we review the various gene replacement strategies for target organs affected

Mark S. Sands; Beverly L. Davidson

2006-01-01

209

2003 Freund Publishing House Ltd. 77 PROSPECTS FOR GENE THERAPY  

E-print Network

to find new ways to perform gene therapy in order to cure genetic diseases. For example, the Reprint derived from the inner cell mass of the early pre-implantation embryo, for a multitude of diseases, including Parkinson's and Alzheimer's, though this area is mired in debate /7,8/. Recent achievements

Avraham, Karen

210

Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs  

E-print Network

Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs Katherine Parker Ponder 12, 2002) Dogs with mucopolysaccharidosis VII (MPS VII) were injected in- travenously at 2­3 days alone, and two dogs received hepatocyte growth factor (HGF) before RV in an attempt to increase

Ponder, Katherine P.

211

The challenge of vector development in gene therapy  

Microsoft Academic Search

Gene therapy is the treatment of diseases based on the transfer of genetic information. Agents that carry or deliver DNA to target cells are called vectors (Latin vector: carrier, deliverer). Ideally, a vector should accommodate an unlimited amount of inserted DNA, lack the ability of autonomous replication of its own DNA, be easily manufac- tured, and be available in concentrated

S. U. Dani

1999-01-01

212

Gutless adenoviral vectors — Promising tools for gene therapy  

Microsoft Academic Search

Summary  \\u000a Background: Progress in gene therapy depends on establishing the appropriate gene transfer methods. The most efficient vehicles for\\u000a the delivery of foreign genes to the target tissues are modified adenoviruses.\\u000a \\u000a \\u000a Methods: Adenoviral vectors of the first generation despite the high infection efficiency, have an essential drawback: They induce\\u000a a strong immune response, which excludes them from clinical trials.\\u000a \\u000a \\u000a \\u000a \\u000a Results:

Alicja Jozkowicz; J. Dulak; J. Nanobashvili; P. Polterauer; M. Prager; I. Huk

2002-01-01

213

Gene therapy (somatic cell), Mario CapecchiSite: DNA Interactive (www.dnai.org)  

NSDL National Science Digital Library

Interviewee: Mario Capecchi DNAi Location: Applications>Genes and Medicine>Gene targeting>Possibilities Cell therapy (somatic) Mario Capecchi talks about the possibility of correcting genetic defects.

2008-03-26

214

Zinc Finger Nucleases: Tailor-made for Gene Therapy  

PubMed Central

Genome editing with the use of zinc finger nucleases has been successfully applied to variety of a eukaryotic cells. Furthermore, the proof of concept for this approach has been extended to diverse animal models from Drosophila to mice. Engineered zinc finger nucleases are able to target specifically and manipulate disease-causing genes through site-specific double strand DNA breaks followed by non-homologous end joining or homologous recombination mechanisms. Consequently, this technology has considerable flexibility that can result in either a gain or loss of function of the targeted gene. In addition to this flexibility, gene therapy by zinc finger nucleases may enable persistent long term gene modification without continuous transfection- a potential advantage over RNA interference or direct gene inhibitors. With systemic viral delivery systems, this gene-editing approach corrected the mutant factor IX in models of mouse hemophilia. Moreover, phase I clinical trials have been initiated with zinc finger nucleases in patients with glioblastoma and HIV. Thus, this emerging field has significant promise as a therapeutic strategy for human genetic diseases, infectious diseases and oncology. In this article, we will review recent advances and potential risks in zinc finger nuclease gene therapy. PMID:24155503

Chou, S.-T.; Leng, Qixin; Mixson, A. J.

2012-01-01

215

Vector platforms for gene therapy of inherited retinopathies.  

PubMed

Inherited retinopathies (IR) are common untreatable blinding conditions. Most of them are inherited as monogenic disorders, due to mutations in genes expressed in retinal photoreceptors (PR) and in retinal pigment epithelium (RPE). The retina's compatibility with gene transfer has made transduction of different retinal cell layers in small and large animal models via viral and non-viral vectors possible. The ongoing identification of novel viruses as well as modifications of existing ones based either on rational design or directed evolution have generated vector variants with improved transduction properties. Dozens of promising proofs of concept have been obtained in IR animal models with both viral and non-viral vectors, and some of them have been relayed to clinical trials. To date, recombinant vectors based on the adeno-associated virus (AAV) represent the most promising tool for retinal gene therapy, given their ability to efficiently deliver therapeutic genes to both PR and RPE and their excellent safety and efficacy profiles in humans. However, AAVs' limited cargo capacity has prevented application of the viral vector to treatments requiring transfer of genes with a coding sequence larger than 5 kb. Vectors with larger capacity, i.e. nanoparticles, adenoviral and lentiviral vectors are being exploited for gene transfer to the retina in animal models and, more recently, in humans. This review focuses on the available platforms for retinal gene therapy to fight inherited blindness, highlights their main strengths and examines the efforts to overcome some of their limitations. PMID:25124745

Trapani, Ivana; Puppo, Agostina; Auricchio, Alberto

2014-11-01

216

Periodontal therapy alters gene expression of peripheral blood monocytes  

PubMed Central

Aims We investigated the effects of periodontal therapy on gene expression of peripheral blood monocytes. Methods Fifteen patients with periodontitis gave blood samples at four time points: 1 week before periodontal treatment (#1), at treatment initiation (baseline, #2), 6-week (#3) and 10-week post-baseline (#4). At baseline and 10 weeks, periodontal status was recorded and subgingival plaque samples were obtained. Periodontal therapy (periodontal surgery and extractions without adjunctive antibiotics) was completed within 6 weeks. At each time point, serum concentrations of 19 biomarkers were determined. Peripheral blood monocytes were purified, RNA was extracted, reverse-transcribed, labelled and hybridized with AffymetrixU133Plus2.0 chips. Expression profiles were analysed using linear random-effects models. Further analysis of gene ontology terms summarized the expression patterns into biologically relevant categories. Differential expression of selected genes was confirmed by real-time reverse transcriptase-polymerase chain reaction in a subset of patients. Results Treatment resulted in a substantial improvement in clinical periodontal status and reduction in the levels of several periodontal pathogens. Expression profiling over time revealed more than 11,000 probe sets differentially expressed at a false discovery rate of <0.05. Approximately 1/3 of the patients showed substantial changes in expression in genes relevant to innate immunity, apoptosis and cell signalling. Conclusions The data suggest that periodontal therapy may alter monocytic gene expression in a manner consistent with a systemic anti-inflammatory effect. PMID:17716309

Papapanou, Panos N.; Sedaghatfar, Michael H.; Demmer, Ryan T.; Wolf, Dana L.; Yang, Jun; Roth, Georg A.; Celenti, Romanita; Belusko, Paul B.; Lalla, Evanthia; Pavlidis, Paul

2009-01-01

217

76 FR 18768 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...Docket No. FDA-2011-N-0002] Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food...closed to the public. Name of Committee: Cellular, Tissue, and Gene Therapies Advisory Committee. General Function of the...

2011-04-05

218

78 FR 15726 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...Administration [Docket No. FDA-2013-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food...closed to the public. Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General Function of the...

2013-03-12

219

76 FR 64951 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...Administration [Docket No. FDA-2011-N-0002] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food...open to the public. Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General Function of the...

2011-10-19

220

77 FR 73472 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...Administration [Docket No. FDA-2012-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food...closed to the public. Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General Function of the...

2012-12-10

221

76 FR 49774 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting  

Federal Register 2010, 2011, 2012, 2013

...Administration [Docket No. FDA-2011-N-0002] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food...open to the public. Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General Function of the...

2011-08-11

222

Liver-directed Neonatal Gene Therapy Prevents Cardiac, Bone, Ear, and Eye Disease in  

E-print Network

Words: gene therapy, lysosomal storage disease, retroviral vector, mucopolysaccharidosis, glycosaminoglycan, neonatal, liver, mannose 6-phosphate INTRODUCTION Lysosomal storage diseases (LSD) haveLiver-directed Neonatal Gene Therapy Prevents Cardiac, Bone, Ear, and Eye Disease

Ponder, Katherine P.

223

Clinicians’ Expectations for Gene-Driven Cancer Therapy  

PubMed Central

A new era of medicine is rapidly approaching, which will change not only pathological diagnosis but also medical decision-making. This paper raises the question of how well prepared doctors are to address the new issues that will soon confront them. The human genome has been completely sequenced and general understanding about cancer biology has increased enormously with understanding that unregulated gene function and complicated changes in signal pathways are related to uncontrolled cell growth. Thus, gene-driven therapy involving alterations to genes are recognized to present new therapy options. This advance will necessitate major changes to the decision-making aspect of physicians. This article focuses on defining the pertinent changes and addressing what they mean for practicing physicians. PMID:25574148

Jekunen, Antti

2014-01-01

224

Fluorescent Molecular Imaging and Dosimetry Tools in Photodynamic Therapy  

PubMed Central

Measurement of fluorescence and phosphorescence in vivo is readily used to quantify the concentration of specific species that are relevant to photodynamic therapy. However, the tools to make the data quantitatively accurate vary considerably between different applications. Sampling of the signal can be done with point samples, such as specialized fiber probes or from bulk regions with either imaging or sampling, and then in broad region image-guided manner. Each of these methods is described below, the application to imaging photosensitizer uptake is discussed, and developing methods to image molecular responses to therapy are outlined. PMID:20552350

Pogue, Brian W.; Samkoe, Kimberley S.; Gibbs-Strauss, Summer L.; Davis, Scott C.

2013-01-01

225

MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas  

PubMed Central

Multiple endocrine neoplasia type 1 (MEN1) is characterized by the combined occurrence of pituitary, pancreatic and parathyroid tumors showing loss of heterozygosity in the putative tumor suppressor gene MEN1. This gene encodes the protein menin, the overexpression of which inhibits cell proliferation in vitro. In this study, we conducted a preclinical evaluation of MEN1 gene therapy in pituitary tumors of Men1+/? mice, using a recombinant non-replicating adenoviral serotype 5 vector that contained the murine Men1 cDNA under control of a cytomegalovirus promoter (Men1.rAd5). Pituitary tumours in 55 Men1+/? female mice received a transauricular, intratumoral injection of Men1.rAd5 or control treatments, followed by 5-bromo-2-deoxyuridine (BrdU) in drinking water for four weeks before magnetic resonance imaging (MRI) and immunohistochemical analysis. Immediate procedure-related and four-week mortalities were similar in all groups, indicating that the adenoviral gene therapy was not associated with a higher mortality. Menin expression was higher in the Men1.rAd5-treated mice when compared to other groups. Daily proliferation rates assessed by BrdU incorporation were reduced significantly in Men1.rAd5-injected tumors relative to control treated tumors. In contrast, apoptotic rates, immune T cell response and tumor volumes remained similar in all groups. Our findings establish that MEN1 gene replacement therapy can generate menin expression in pituitary tumors, and significantly reduce tumor cell proliferation. PMID:22915754

Walls, Gerard V.; Lemos, Manuel C; Javid, Mahsa; Bazan-Peregrino, Miriam; Jeyabalan, Jeshmi; Reed, Anita A. C.; Harding, Brian; Tyler, Damian J.; Stuckey, Daniel J.; Piret, Sian; Christie, Paul T.; Ansorge, Olaf; Clarke, Kieran; Seymour, Len; Thakker, Rajesh V.

2012-01-01

226

Recombinant Adenovirus Deleted of All Viral Genes for Gene Therapy of Cystic Fibrosis  

Microsoft Academic Search

Recombinant adenoviruses are being developed for gene therapy of inherited disorders such as cystic fibrosis because they efficiently transduce recombinant genes into nondividing cellsin vivo.First generation recombinant adenoviruses, rendered defective by deletion of sequences spanning E1a and E1b, express low levels of early and late viral genes that activate destructive cellular immune responses. Current strategies for improving recombinant adenoviruses attempt

KRISHNA J. FISHER; HESTER CHOI; JOHN BURDA; SHU-JEN CHEN; JAMES M. WILSON

1996-01-01

227

MRI Reporter Genes: Application to Imaging of Cell Survival, Proliferation, Migration, and Differentiation  

PubMed Central

Molecular imaging strives to detect molecular events at the level of the whole organism. In some cases, the molecule of interest can be detected either directly, or through the use of targeted contrast media. However many genes and proteins, and particularly those located in intracellular compartments, are not accessible for targeted agents. The transcriptional regulation of these genes can never the less be detected, though indirectly, through the use of reporter genes encoding for readily detectable proteins. Such reporter proteins can be expressed in the tissue of interest by genetically introducing the reporter gene in the target cells. Imaging of reporter genes has become a powerful tool in modern biomedical research. Typically, expression of fluorescent or bioluminescent proteins, or the reaction product of expressed enzymes and exogenous substrates, are examined using in vitro histological methods, or in vivo whole body imaging methods. Recent advances in MRI reporter gene methods raise the possibility that MRI could become a powerful tool for concomitant high resolution anatomical and functional imaging and for imaging of reporter gene activity. An immediate application of MRI reporter gene methods is for monitoring gene expression patterns in gene therapy and for in vivo imaging of the survival, proliferation, migration, and differentiation of pluripotent or multipotent cells used in cell based regenerative therapies for cancer, myocardial infarction, and neural degeneration. In this review, we characterize the variety of MRI reporter gene methods based on their applicability to report cell survival/proliferation, cell migration, and cell differentiation. In particular, we discuss which methods are best suited for translation to clinical use in regenerative therapies. PMID:23225197

Vandsburger, Moriel H; Radoul, Marina; Cohen, Batya; Neeman, Michal

2013-01-01

228

Current status of gene therapy for ?-1 antitrypsin deficiency.  

PubMed

Introduction: As a common monogenic disease, ?-1 antitrypsin (AAT) deficiency has undergone thorough investigation for the development of gene therapy. The most common pathology associated with AAT deficiency occurs in the lung, where the loss of function due to impaired secretion of mutant AAT prevents the inhibition of neutrophil elastase and leads to loss of elastin content from the alveolar interstitium. Areas covered: Current treatment in the USA consists of recurrent intravenous protein replacement therapy to augment serum AAT levels. In an attempt to replace recurring treatments with a single dose of gene therapy, recombinant adenovirus, plasmid, and recombinant adeno-associated virus (rAAV) vectors have been investigated as vectors for transgene delivery. Expert opinion: Large strides in gene therapy for AAT deficiency lung disease have led to the development of rAAV1-AAT capable of producing sustained serum AAT levels in clinical trials after intramuscular administration in humans at 3% of the target level. Further increases in levels are anticipated as limb perfusion targets greater muscle mass. The future roles of intrapleural and airway delivery, miRNA-expressing vectors, iPS cell platforms, and genome editing are anticipated. PMID:25363251

Loring, Heather S; Flotte, Terence R

2014-11-01

229

Mucopolysaccharidosis I Cats Mount a Cytotoxic T Lymphocyte Response after Neonatal Gene Therapy  

E-print Network

Mucopolysaccharidosis I Cats Mount a Cytotoxic T Lymphocyte Response after Neonatal Gene Therapy, as mucopolysaccharidosis I (MPS I) mice that received neonatal intravenous gene therapy with a high dose of a canine A after neonatal gene therapy. We conclude that cats, but not dogs, mount a potent CTL response to canine

Ponder, Katherine P.

230

ErikaCheck,Washington The troubled field of gene therapy was  

E-print Network

ErikaCheck,Washington The troubled field of gene therapy was dealt a fresh blow this week, after by geneticist Mark Kay at Stanford University, California, examined a modified virus used in gene-therapy trials to causethesameproblemsthatledtocancerin anunrelatedgene-therapytriallastyear. In gene therapy, doctors use a gutted virus as a `vector

Kay, Mark A.

231

HUMAN GENE THERAPY 18:871880 (October 2007) Mary Ann Liebert, Inc.  

E-print Network

HUMAN GENE THERAPY 18:871­880 (October 2007) © Mary Ann Liebert, Inc. DOI: 10.1089/hum.2007 therapy of dominantly active mutant alleles, and to the investigation of normal gene function in animal delivery of RNAi constructs offers a powerful and versatile approach for both gene therapy and the analysis

Kay, Mark A.

232

Progress in developing cationic systems for non-viral vector systemic gene therapy against cancer  

E-print Network

1 Progress in developing cationic systems for non-viral vector systemic gene therapy against cancer;29(24-25):3477-96" DOI : 10.1016/j.biomaterials.2008.04.036 #12;2 Abstract: Initially, gene therapy was viewed with these carriers, the aim of this review is to describe the "perfect vector" for systemic gene therapy against

Paris-Sud XI, Université de

233

HUMAN GENE THERAPY 12:563573 (March 20, 2001) Mary Ann Liebert, Inc.  

E-print Network

HUMAN GENE THERAPY 12:563­573 (March 20, 2001) Mary Ann Liebert, Inc. CMV-b-Actin Promoter Directs,4 and KATHERINE PARKER PONDER1,5 ABSTRACT Although AAV vectors show promise for hepatic gene therapy, the optimal), which derived from both liver and muscle. We conclude that neonatal gene therapy with an AAV vector

Ponder, Katherine P.

234

HUMAN GENE THERAPY 14:12551264 (September 1, 2003) Mary Ann Liebert, Inc.  

E-print Network

HUMAN GENE THERAPY 14:1255­1264 (September 1, 2003) © Mary Ann Liebert, Inc. System, PETER D. PENG, and MARK A. KAY ABSTRACT Gene therapy has been proposed as an alternative strategy, thereby considerably enhancing the therapeutic win- dow of gene therapy. 1255 OVERVIEW SUMMARY We have

Kay, Mark A.

235

The American Society of Gene & Cell Therapy letter to the editor  

E-print Network

© The American Society of Gene & Cell Therapy letter to the editor large budgets by various contrasts sharply with the relatively limited budgets that have been available for gene therapy research. Typically, most gene therapy researchers work as small teams on a specific disease with a relatively small

Barbas III, Carlos F.

236

75 FR 54351 - Cell and Gene Therapy Clinical Trials in Pediatric Populations; Public Workshop  

Federal Register 2010, 2011, 2012, 2013

...Administration [Docket No. FDA-2010-N-0001] Cell and Gene Therapy Clinical Trials in Pediatric...announcing a public workshop entitled ``Cell and Gene Therapy Clinical Trials in Pediatric...stakeholders regarding best practices related to cell and gene therapy clinical trials in...

2010-09-07

237

Multimodality Molecular Imaging of Stem Cells Therapy for Stroke  

PubMed Central

Stem cells have been proposed as a promising therapy for treating stroke. While several studies have demonstrated the therapeutic benefits of stem cells, the exact mechanism remains elusive. Molecular imaging provides the possibility of the visual representation of biological processes at the cellular and molecular level. In order to facilitate research efforts to understand the stem cells therapeutic mechanisms, we need to further develop means of monitoring these cells noninvasively, longitudinally and repeatedly. Because of tissue depth and the blood-brain barrier (BBB), in vivo imaging of stem cells therapy for stroke has unique challenges. In this review, we describe existing methods of tracking transplanted stem cells in vivo, including magnetic resonance imaging (MRI), nuclear medicine imaging, and optical imaging (OI). Each of the imaging techniques has advantages and drawbacks. Finally, we describe multimodality imaging strategies as a more comprehensive and potential method to monitor transplanted stem cells for stroke. PMID:24222920

Zhang, Hong; Tian, Mei

2013-01-01

238

Rhodamine based plasmid DNA nanoparticles for mitochondrial gene therapy.  

PubMed

Conventional treatments for patients suffering from mitochondrial cytopathies are, in most of the cases, inefficient and there is, until now, no effective cure. Mitochondrial gene therapy can be seen as a valuable approach to reestablish normal metabolic function, adding a new perspective of treatment for mitochondrial-related diseases. We developed novel mitochondrial-targeted plasmid DNA nanoparticles by incorporation of rhodamine 123, a fluorescent amphiphile with mitochondria affinity. These nanocarriers have suitable sizes for gene therapy purposes, are biocompatible and are able to protect the encapsulated pDNA from nucleases digestion. Furthermore, the pDNA vectors were easily internalized intodifferent cell linesand targeted delivery to mitochondria was confirmed by fluorescence confocal microscopy. In addition, p53 protein inexpression, mediated by rhodamine nanoparticles, demonstrates the ability of the proposed system to target mitochondria; due to the different genetic code in mitochondria, p53 protein cannot be expressed. Overall, the presented model pDNA constructs possess interesting properties as gene delivery systems and their mitochondrial target ability might have a profound relevance for further engineering of adequate vectors to be applied in mitochondrial gene therapy field. PMID:24967548

Santos, João; Sousa, Fani; Queiroz, João; Costa, Diana

2014-09-01

239

Gene mutations and molecularly targeted therapies in acute myeloid leukemia.  

PubMed

Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations. PMID:23358589

Hatzimichael, Eleftheria; Georgiou, Georgios; Benetatos, Leonidas; Briasoulis, Evangelos

2013-01-01

240

Roadmap: Radiologic Imaging Sciences -Radiation Therapy (with AAS Radiologic Technology)  

E-print Network

Roadmap: Radiologic Imaging Sciences - Radiation Therapy (with AAS Radiologic Technology) ­ Bachelor of Radiologic and Imaging Sciences Technology [RE-BRIT-RIS-RTAA] Regional College Catalog Year Hours] Note: Students must have earned an AAS degree in Radiologic Technology (36 semester credits from

Sheridan, Scott

241

Combining Cytotoxic and Immune-Mediated Gene Therapy to Treat Brain Tumors  

PubMed Central

Glioblastoma (GBM) is a type of intracranial brain tumor, for which there is no cure. In spite of advances in surgery, chemotherapy and radiotherapy, patients die within a year of diagnosis. Therefore, there is a critical need to develop novel therapeutic approaches for this disease. Gene therapy, which is the use of genes or other nucleic acids as drugs, is a powerful new treatment strategy which can be developed to treat GBM. Several treatment modalities are amenable for gene therapy implementation, e.g. conditional cytotoxic approaches, targeted delivery of toxins into the tumor mass, immune stimulatory strategies, and these will all be the focus of this review. Both conditional cytotoxicity and targeted toxin mediated tumor death, are aimed at eliminating an established tumor mass and preventing further growth. Tumors employ several defensive strategies that suppress and inhibit anti-tumor immune responses. A better understanding of the mechanisms involved in eliciting anti-tumor immune responses has identified promising targets for immunotherapy. Immunotherapy is designed to aid the immune system to recognize and destroy tumor cells in order to eliminate the tumor burden. Also, immune-therapeutic strategies have the added advantage that an activated immune system has the capability of recognizing tumor cells at distant sites from the primary tumor, therefore targeting metastasis distant from the primary tumor locale. Pre-clinical models and clinical trials have demonstrated that in spite of their location within the central nervous system (CNS), a tissue described as ‘immune privileged’, brain tumors can be effectively targeted by the activated immune system following various immunotherapeutic strategies. This review will highlight recent advances in brain tumor immunotherapy, with particular emphasis on advances made using gene therapy strategies, as well as reviewing other novel therapies that can be used in combination with immunotherapy. Another important aspect of implementing gene therapy in the clinical arena is to be able to image the targeting of the therapeutics to the tumors, treatment effectiveness and progression of disease. We have therefore reviewed the most exciting non-invasive, in vivo imaging techniques which can be used in combination with gene therapy to monitor therapeutic efficacy over time. PMID:16248789

Curtin, James F.; King, Gwendalyn D.; Candolfi, Marianela; Greeno, Remy B.; Kroeger, Kurt M.; Lowenstein, Pedro R.; Castro, Maria G.

2006-01-01

242

Application of electroporation gene therapy: past, current, and future.  

PubMed

Twenty-five years after the publication of the first report on gene transfer in vitro in cultured cells by the means of electric pulse delivery, reversible cell electroporation for gene transfer and gene therapy (DNA electrotransfer) is at a crossroad in its development. Present knowledge on the effects of cell exposure to appropriate electric field pulses, particularly at the level of the cell membrane, is reported here as an introduction to the large range of applications described in this book. The importance of the models of electric field distribution in tissues and of the correct choice of electrodes and applied voltages is highlighted. The mechanisms involved in DNA electrotransfer, which include cell electropermeabilization and DNA electrophoresis, are also surveyed. The feasibility of electric pulse for gene transfer in humans is discussed taking into account that electric pulse delivery is already regularly used for localized drug delivery in the treatment of cutaneous and subcutaneous solid tumors by electrochemotherapy. Because recent technological developments have made DNA electrotransfer more efficient and safer, this nonviral gene therapy approach is now ready to reach the clinical stage. A good understanding of DNA electrotransfer principles and a respect for safe procedures will be key elements for the successful future transition of DNA electrotransfer to the clinics. PMID:18370187

Mir, Lluis M

2008-01-01

243

Gene therapy for severe combined immunodeficiency: are we there yet?  

PubMed Central

Inherited and acquired diseases of the hematopoietic system can be cured by allogeneic hematopoietic stem cell transplantation. This treatment strategy is highly successful when an HLA-matched sibling donor is available, but if not, few therapeutic options exist. Gene-modified, autologous bone marrow transplantation can circumvent the severe immunological complications that occur when a related HLA-mismatched donor is used and thus represents an attractive alternative. In this review, we summarize the advantages and limitations associated with the use of gene therapy to cure SCID. Insertional mutagenesis and technological improvements aimed at increasing the safety of this strategy are also discussed. PMID:17549248

Cavazzana-Calvo, Marina; Fischer, Alain

2007-01-01

244

Prevention of peritoneal adhesions: A promising role for gene therapy  

PubMed Central

Adhesions are the most frequent complication of abdominopelvic surgery, yet the extent of the problem, and its serious consequences, has not been adequately recognized. Adhesions evolved as a life-saving mechanism to limit the spread of intraperitoneal inflammatory conditions. Three different pathophysiological mechanisms can independently trigger adhesion formation. Mesothelial cell injury and loss during operations, tissue hypoxia and inflammation each promotes adhesion formation separately, and potentiate the effect of each other. Studies have repeatedly demonstrated that interruption of a single pathway does not completely prevent adhesion formation. This review summarizes the pathogenesis of adhesion formation and the results of single gene therapy interventions. It explores the promising role of combinatorial gene therapy and vector modifications for the prevention of adhesion formation in order to stimulate new ideas and encourage rapid advancements in this field. PMID:22171139

Atta, Hussein M

2011-01-01

245

GENE AND CELL-MEDIATED THERAPIES FOR MUSCULAR DYSTROPHY  

PubMed Central

Duchenne muscular dystrophy (DMD) is a devastating muscle disorder that affects 1 in 3500 boys. Despite years of research and considerable progress in understanding the molecular mechanism of the disease and advancement of therapeutic approaches, there is no cure for DMD. The current treatment options are limited to physiotherapy and corticosteroids, and although they provide a substantial improvement in affected children, they only slow the course of the disorder. On a more optimistic note, the most recent approaches either significantly alleviate or eliminate muscular dystrophy in murine and canine models of DMD and importantly, many of them are being tested in early phase human clinical trials. This review summarizes advancements that have been made in viral and non-viral gene therapy as well as stem cell therapy for DMD with a focus on the replacement and repair of the affected dystrophin gene. PMID:23553671

Konieczny, Patryk; Swiderski, Kristy; Chamberlain, Jeffrey S.

2014-01-01

246

Genomic discovery of potent chromatin insulators for human gene therapy.  

PubMed

Insertional mutagenesis and genotoxicity, which usually manifest as hematopoietic malignancy, represent major barriers to realizing the promise of gene therapy. Although insulator sequences that block transcriptional enhancers could mitigate or eliminate these risks, so far no human insulators with high functional potency have been identified. Here we describe a genomic approach for the identification of compact sequence elements that function as insulators. These elements are highly occupied by the insulator protein CTCF, are DNase I hypersensitive and represent only a small minority of the CTCF recognition sequences in the human genome. We show that the elements identified acted as potent enhancer blockers and substantially decreased the risk of tumor formation in a cancer-prone animal model. The elements are small, can be efficiently accommodated by viral vectors and have no detrimental effects on viral titers. The insulators we describe here are expected to increase the safety of gene therapy for genetic diseases. PMID:25580597

Liu, Mingdong; Maurano, Matthew T; Wang, Hao; Qi, Heyuan; Song, Chao-Zhong; Navas, Patrick A; Emery, David W; Stamatoyannopoulos, John A; Stamatoyannopoulos, George

2015-02-01

247

Effective Gene Therapy in a Mouse Model of Prion Diseases  

Microsoft Academic Search

Classical drug therapies against prion diseases have encountered serious difficulties. It has become urgent to develop radically different therapeutic strategies. Previously, we showed that VSV-G pseudotyped FIV derived vectors carrying dominant negative mutants of the PrP gene are efficient to inhibit prion replication in chronically prion-infected cells. Besides, they can transduce neurons and cells of the lymphoreticular system, highlighting their

Karine Toupet; Valérie Compan; Carole Crozet; Chantal Mourton-Gilles; Nadine Mestre-Francés; Françoise Ibos; Pierre Corbeau; Jean-Michel Verdier; Véronique Perrier

2008-01-01

248

Induction of B-cell tolerance by retroviral gene therapy.  

PubMed

The primary immunologic barrier to overcome before clinical xenotransplantation can be successful is rejection mediated by preformed natural antibodies in the host, directed toward a single carbohydrate epitope Galalpha1-3Galbeta1-4GlcNAc-R (alphaGal) present on porcine tissue, encoded for by the enzyme glucosyltransferase UDP galactose:beta-D-galactosyl-1, 4-N-acetyl-D-glucosaminide alpha(1-3)galactosyltransferase (EC 2.4.1. 151) or simply alphaGT. Although we have shown previously that a gene therapy approach could be used to prevent production of natural antibodies specific for alphaGal, the ability to induce and maintain tolerance after rigorous antigen challenge would be required if similar approaches are to be used clinically. Here, we demonstrate in alphaGT knockout mice (GT(0) mice), which, like humans, contain in their serum antibodies that bind alphaGal, that the efficient transduction and expression of a retrovirally transduced alphaGT gene in bone marrow-derived cells induces stable long-term tolerance to the alphaGal epitope. GT(0) mice reconstituted with alphaGT-transduced bone marrow cells were unable to produce antibodies that bind alphaGal after extensive immunization with pig cells. Furthermore, using ELISPOT assays, we were unable to detect the presence of B cells that produce alphaGal reactive antibodies after immunization, suggesting that such B cells were eliminated from the immunologic repertoire after gene therapy. Interestingly, after tolerance to alphaGal is induced by gene therapy, the antiporcine non-alphaGal humoral response changes from a predominantly IgM to an IgG response. This suggests that once the natural antibody barrier is eliminated by the induction of tolerance, the antipig response changes to a typical T-cell-dependent response involving isotype switching. Thus, gene therapy approaches may be used to overcome immunologic responses leading to xenograft rejection, and similar gene therapy approaches could be used to overcome autoimmunity. PMID:11049978

Bracy, J L; Iacomini, J

2000-11-01

249

Therapeutic angiogenesis for peripheral artery disease: gene therapy.  

PubMed

Peripheral artery disease is a highly prevalent disease which is characterised by a high unmet medical need particularly in the more advanced stages of disease. Recent advances in the knowledge of the complex regulation of angiogenesis and arteriogenesis and ways to its induction offer hope for a novel strategy that is based on the generation of such new vessels. This strategy termed "therapeutic angiogenesis" is a concept based on the use of angiogenic factors or stem cells or their combination to promote neovascularisation for the treatment of ischaemic tissues. This article reviews both regulation of angiogenesis and the development of therapeutic strategies based on this knowledge using gene therapy. This includes knowledge from animal experiments as well as from phase I and phase II clinical trials. This information may be particularly important at a time when angiogenesis gene therapy enters the stage of phase III clinical testing hopefully leading to the first time approval of this completely new class of drug in the near future. Following articles of this series will review therapeutic angiogenesis approaches based on cytokine therapy and stem cell therapy. PMID:18019272

Nikol, S

2007-08-01

250

Image registration and data fusion in radiation therapy.  

PubMed

This paper provides an overview of image registration and data fusion techniques used in radiation therapy, and examples of their use. They are used at all stages of the patient management process; for initial diagnosis and staging, during treatment planning and delivery, and after therapy to help monitor the patients' response to treatment. Most treatment planning systems now support some form of interactive or automated image registration and provide tools for mapping information, such as tissue outlines and computed dose from one imaging study to another. To complement this, modern treatment delivery systems offer means for acquiring and registering 2D and 3D image data at the treatment unit to aid patient setup. Techniques for adapting and customizing treatments during the course of therapy using 3D and 4D anatomic and functional imaging data are currently being introduced into the clinic. These techniques require sophisticated image registration and data fusion technology to accumulate properly the delivered dose and to analyse possible physiological and anatomical changes during treatment. Finally, the correlation of radiological changes after therapy with delivered dose also requires the use of image registration and fusion techniques. PMID:16980689

Kessler, M L

2006-09-01

251

Neurotrophic gene polymorphisms and response to psychological therapy.  

PubMed

Therapygenetics, the study of genetic determinants of response to psychological therapies, is in its infancy. Here, we investigate whether single-nucleotide polymorphisms in nerve growth factor (NGF) (rs6330) and brain-derived neutrotrophic factor (BDNF) (rs6265) genes predict the response to cognitive behaviour therapy (CBT). Neurotrophic genes represent plausible candidate genes: they are implicated in synaptic plasticity, response to stress, and are widely expressed in brain areas involved in mood and cognition. Allelic variation at both loci has shown associations with anxiety-related phenotypes. A sample of 374 anxiety-disordered children with white European ancestry was recruited from clinics in Reading, UK, and in Sydney, Australia. Participants received manualised CBT treatment and DNA was collected from buccal cells using cheek swabs. Treatment response was assessed at post-treatment and follow-up time points. We report first evidence that children with one or more copies of the T allele of NGF rs6330 were significantly more likely to be free of their primary anxiety diagnosis at follow-up (OR = 0.60 (0.42-0.85), P = 0.005). These effects remained even when other clinically relevant covariates were accounted for (OR = 0.62 (0.41-0.92), P = 0.019). No significant associations were observed between BDNF rs6265 and response to psychological therapy. These findings demonstrate that knowledge of genetic markers has the potential to inform clinical treatment decisions for psychotherapeutic interventions. PMID:22832952

Lester, K J; Hudson, J L; Tropeano, M; Creswell, C; Collier, D A; Farmer, A; Lyneham, H J; Rapee, R M; Eley, T C

2012-01-01

252

The Challenge for Gene Therapy: Innate Immune Response to Adenoviruses  

PubMed Central

Adenoviruses are the most commonly used vectors for gene therapy. Despite the promising safety profile demonstrated in clinical trials, the efficacy of using adenoviruses for gene therapy is poor. A major hurdle to adenoviral-mediated gene therapy is the innate immune system. Cell-mediated recognition of viruses via capsid components or nucleic acids has received significant attention, principally thought to be regulated by the toll-like receptors (TLRs). Antiviral innate immune responses are initiated by the infected cell, which activates the interferon (IFN) response to block viral replication, while simultaneously releasing chemokines to attract neutrophils, mononuclear- and natural killer-cells. While the IFN and cellular recruitment pathways are activated and regulated independently of each other, both are required to overcome immune escape mechanisms by adenoviruses. Recent work has shown that the generation of adenoviral vectors lacking specific transcriptionally-active regions decreases immune system activation and increases the chance for immune escape. In this review, we elucidate how adenoviral vector modifications alter the IFN and innate inflammatory pathway response and propose future targets with clinically-translational relevance. PMID:21399236

Thaci, Bart; Ulasov, Ilya V.; Wainwright, Derek A.; Lesniak, Maciej S.

2011-01-01

253

The challenge for gene therapy: innate immune response to adenoviruses.  

PubMed

Adenoviruses are the most commonly used vectors for gene therapy. Despite the promising safety profile demonstrated in clinical trials, the efficacy of using adenoviruses for gene therapy is poor. A major hurdle to adenoviral-mediated gene therapy is the innate immune system. Cell-mediated recognition of viruses via capsid components or nucleic acids has received significant attention, principally thought to be regulated by the toll-like receptors (TLRs). Antiviral innate immune responses are initiated by the infected cell, which activates the interferon (IFN) response to block viral replication, while simultaneously releasing chemokines to attract neutrophils, mononuclear- and natural killer-cells. While the IFN and cellular recruitment pathways are activated and regulated independently of each other, both are required to overcome immune escape mechanisms by adenoviruses. Recent work has shown that the generation of adenoviral vectors lacking specific transcriptionally-active regions decreases immune system activation and increases the chance for immune escape. In this review, we elucidate how adenoviral vector modifications alter the IFN and innate inflammatory pathway response and propose future targets with clinically-translational relevance. PMID:21399236

Thaci, Bart; Ulasov, Ilya V; Wainwright, Derek A; Lesniak, Maciej S

2011-03-01

254

Gene therapy for the nervous system: challenges and new strategies.  

PubMed

Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson's disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to "permanently" correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber's congenital aumorosis) and Parkinson's disease have shown that gene-based neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics. PMID:25159276

Maguire, Casey A; Ramirez, Servio H; Merkel, Steven F; Sena-Esteves, Miguel; Breakefield, Xandra O

2014-10-01

255

Far-red fluorescence gene reporter tomography for determination of placement and viability of cell-based gene therapies  

PubMed Central

Non-invasive injectable cellular therapeutic strategies based on sustained delivery of physiological levels of BMP-2 for spinal fusion are emerging as promising alternatives, which could provide sufficient fusion without the associated surgical risks. However, these injectable therapies are dependent on bone formation occurring only at the specific target region. In this study, we developed and deployed fluorescence gene reporter tomography (FGRT) to provide information on in vivo cell localization and viability. This information is sought to confirm the ideal placement of the materials with respect to the area where early bone reaction is required, ultimately providing three dimensional data about the future fusion. However, because almost all conventional fluorescence gene reporters require visible excitation wavelengths, current in vivo imaging of fluorescent proteins is limited by high tissue absorption and confounding autofluorescence. We previously administered fibroblasts engineered to produce BMP-2, but is difficult to determine 3-D information of placement prior to bone formation. Herein we used the far-red fluorescence gene reporter, IFP1.4 to report the position and viability of fibroblasts and developed 3-D tomography to provide placement information. A custom small animal, far-red fluorescence tomography system integrated into a commercial CT scanner was used to assess IFP1.4 fluorescence and to demark 3-D placement of encapsulated fibroblasts with respect to the vertebrae and early bone formation as assessed from CT. The results from three experiments showed that the placement of the materials within the spine could be detected. This work shows that in vivo fluorescence gene reporter tomography of cell-based gene therapy is feasible and could help guide cell-based therapies in preclinical models. PMID:24104323

Lu, Yujie; Darne, Chinmay D.; Tan, I-Chih; Zhu, Banghe; Hall, Mary A.; Lazard, ZaWaunyka W.; Davis, Alan R.; Simpson, LaShan; Sevick-Muraca, Eva M.; Olmsted-Davis, Elizabeth A.

2013-01-01

256

The development of gene therapy for the treatment of cancer.  

PubMed Central

OBJECTIVE: The authors sought to develop new treatments for patients with cancer based on the genetic modification of immune lymphocytes and tumor cells designed to increase the host immune reaction against growing cancers. METHODS: Retroviral-mediated gene transduction was used to introduce genes into tumor-infiltrating lymphocytes (TIL), and these genetically altered TIL were administered to patients with cancer. Genes coding for cytokines were introduced into tumor cells, and these cells were used to immunize patients against their autologous cancers. RESULTS: In initial studies, the gene for neomycin phosphotransferase was introduced into the TIL of ten patients with advanced cancer to study the survival and distribution of TIL in humans. These studies showed that retroviral gene transduction is a safe and practical method for adding genes to human cells and led to clinical trials in which the gene for tumor necrosis factor (TNF) was inserted into TIL in an effort to increase their therapeutic effectiveness. Phase I trials are currently underway using TIL that secrete up to 100 times the normal level of TNF. More recently, animal experiments have revealed that transduction of tumor cells with cytokine genes can enhance tumor immunogenicity and, thus, increase the recognition of the tumor as foreign by the host. Clinical trials based on these observations have begun in which patients are immunized against their own autologous tumors that were transduced with the genes for TNF or interleukin-2. CONCLUSIONS: Attempts at gene therapy for cancer are underway and have opened new possibilities for the development of cancer treatments. PMID:8215637

Rosenberg, S A; Anderson, W F; Blaese, M; Hwu, P; Yannelli, J R; Yang, J C; Topalian, S L; Schwartzentruber, D J; Weber, J S; Ettinghausen, S E

1993-01-01

257

Phase contrast portal imaging for image-guided microbeam radiation therapy  

NASA Astrophysics Data System (ADS)

High-dose synchrotron microbeam radiation therapy is a unique treatment technique used to destroy tumors without severely affecting circumjacent healthy tissue. We applied a phase contrast technique to portal imaging in preclinical microbeam radiation therapy experiments. Phase contrast portal imaging is expected to enable us to obtain higherresolution X-ray images at therapeutic X-ray energies compared to conventional portal imaging. Frontal view images of a mouse head sample were acquired in propagation-based phase contrast imaging. The phase contrast images depicted edge-enhanced fine structures of the parietal bones surrounding the cerebrum. The phase contrast technique is expected to be effective in bony-landmark-based verification for image-guided radiation therapy.

Umetani, Keiji; Kondoh, Takeshi

2014-03-01

258

Image-guided focal therapy for prostate cancer.  

PubMed

The adoption of routine prostate specific antigen screening has led to the discovery of many small and low-grade prostate cancers which have a low probability of causing mortality. These cancers, however, are often treated with radical therapies resulting in long-term side effects. There has been increasing interest in minimally invasive focal therapies to treat these tumors. While imaging modalities have improved rapidly over the past decade, similar advances in image-guided therapy are now starting to emerge--potentially achieving equivalent oncologic efficacy while avoiding the side effects of conventional radical surgery. The purpose of this article is to review the existing literature regarding the basis of various focal therapy techniques such as cryotherapy, microwave, laser, and high intensity focused ultrasound, and to discuss the results of recent clinical trials that demonstrate early outcomes in patients with prostate cancer. PMID:25205025

Sankineni, Sandeep; Wood, Bradford J; Rais-Bahrami, Soroush; Walton Diaz, Annerleim; Hoang, Anthony N; Pinto, Peter A; Choyke, Peter L; Türkbey, Bar??

2014-11-01

259

Androgen receptor gene and hormonal therapy failure of prostate cancer.  

PubMed Central

Androgen receptor (AR) is a nuclear transcription factor that binds male sex steroids and mediates the biological effects of these hormones to the target cells, such as the epithelial cells of the prostate gland, by activating transcription of androgen-dependent genes. Withdrawal of androgens or the peripheral blockade of androgen action remain the critical therapeutic options for the treatment of advanced prostate cancer. However, after initial regression, many prostate cancers become hormone refractory and progress further with eventual fatal outcome. Understanding the mechanisms of tumor progression and endocrine therapy failure is an important goal. A large number of different molecular mechanisms may be responsible for development of hormone-refractory recurrent tumors. Many of these involve the AR gene and its complex downstream signaling pathways. The role of AR mutations and altered transactivational properties of the receptor have received the most attention as causative factors for progression. However, other mechanisms, such as AR gene amplification and overexpression or increased local bioconversion of androgens, may contribute to the development of progression by mechanisms that involve androgen-dependent cell growth. Here we review the role of the AR gene and its putative downstream effector pathways during human prostate cancer progression and endocrine therapy failure. PMID:9422516

Koivisto, P.; Kolmer, M.; Visakorpi, T.; Kallioniemi, O. P.

1998-01-01

260

Current perspectives on imaging cardiac stem cell therapy.  

PubMed

Molecular imaging is a new discipline that makes possible the noninvasive visualization of cellular and molecular processes in living subjects. In the field of cardiovascular regenerative therapy, imaging cell fate after transplantation is a high priority in both basic research and clinical translation. For cell-based therapy to truly succeed, we must be able to track the locations of delivered cells, the duration of cell survival, and any potential adverse effects. The insights gathered from basic research imaging studies will yield valuable insights into better designs for clinical trials. This review highlights the different types of stem cells used for cardiovascular repair, the development of various imaging modalities to track their fate in vivo, and the challenges of clinical translation of cardiac stem cell imaging in the future. PMID:20395348

Wu, Joseph C; Abraham, M Roselle; Kraitchman, Dara L

2010-05-01

261

New strategy for monitoring targeted therapy: molecular imaging  

PubMed Central

Targeted therapy is becoming an increasingly important component in the treatment of cancer. How to accurately monitor targeted therapy has been crucial in clinical practice. The traditional approach to monitor treatment through imaging has relied on assessing the change of tumor size by refined World Health Organization criteria, or more recently, by the Response Evaluation Criteria in Solid Tumors. However, these criteria, which are based on the change of tumor size, show some limitations for evaluating targeted therapy. Currently, genetic alterations are identified with prognostic as well as predictive potential concerning the use of molecularly targeted drugs. Conversely, considering the limitations of invasiveness and the issue of expression heterogeneity, molecular imaging is better able to assay in vivo biologic processes noninvasively and quantitatively, and has been a particularly attractive tool for monitoring treatment in clinical cancer practice. This review focuses on the applications of different kinds of molecular imaging including positron emission tomography-, magnetic resonance imaging-, ultrasonography-, and computed tomography-based imaging strategies on monitoring targeted therapy. In addition, the key challenges of molecular imaging are addressed to successfully translate these promising techniques in the future. PMID:24124361

Teng, Fei-Fei; Meng, Xue; Sun, Xin-Dong; Yu, Jin-Ming

2013-01-01

262

Molecular imaging: the key to advancing cardiac stem cell therapy.  

PubMed

Cardiac stem cell therapy continues to hold promise for the treatment of ischemic heart disease despite the fact that early promising pre-clinical findings have yet to be translated into consistent clinical success. The latest human studies have collectively identified a pressing need to better understand stem cell behavior in humans and called for more incorporation of noninvasive imaging techniques into the design and evaluation of human stem cell therapy trials. This review discusses the various molecular imaging techniques validated to date for studying stem cells in living subjects, with a particular emphasis on their utilities in assessing the acute retention and the long-term survival of transplanted stem cells. These imaging techniques will be essential for advancing cardiac stem cell therapy by providing the means to both guide ongoing optimization and predict treatment response in humans. PMID:23561794

Chen, Ian Y; Wu, Joseph C

2013-08-01

263

Cytokine-based gene therapy of human tumors. An overview.  

PubMed

This review first summarizes the different strategies of gene therapy of cancer and then focuses on the immunological approach. Several studies in animal models with cytokine gene-transduced tumor cells indicate that local cytokine release usually results in tumor growth inhibition. Moreover, in a number of cases vaccination with such cells can reduce growth of established tumors or even cure the tumor-bearing animals. Translation of such a principle in human clinical setting is reported. We have transduced human melanoma cells with genes coding for interleukin (IL)-2, IL-4 or B7-1 and characterized such lines. The phenotype did not change after gene insertion but the functional, immunostimulatory activity of IL-2 or B7-1 gene-transduced melanoma cells was significantly increased compared to that of parental lines. These-lines were then used to vaccinate melanoma patients. Preliminary results of trials with IL-2 gene-transduced cells are presented which indicate a weak clinical response and the activation of a melanoma-specific cytotoxic T lymphocyte response in a low percentage of patients. PMID:9158940

Parmiani, G; Arienti, F; Sulé-Suso, J; Melani, C; Colombo, M P; Ramakrishna, V; Belli, F; Mascheroni, L; Rivoltini, L; Cascinelli, N

1996-01-01

264

Imaging Biomarkers for Intra-arterial Stroke Therapy  

PubMed Central

Despite high rates of early revascularization with intra-arterial stroke therapy, the clinical efficacy of this approach has not been clearly demonstrated. Neuroimaging biomarkers will be useful in future trials for patient selection and for outcomes evaluation. To identify patients who are likely to benefit from intra-arterial therapy, the combination of vessel imaging, infarct size quantification and degree of neurologic deficit appears critical. Perfusion imaging may be useful in specific circumstances, but requires further validation. For measuring treatment outcomes, surrogate biomarkers that appear suitable are angiographic reperfusion as measured by the modified Thrombolysis in Cerebral Infarction scale and final infarct volume. PMID:24932316

Berkhemer, Olvert A.; Kamalian, Shervin; González, R. Gilberto; Majoie, Charles B. L. M.; Yoo, Albert J.

2014-01-01

265

Treating hearing disorders with cell and gene therapy  

NASA Astrophysics Data System (ADS)

Hearing loss is an increasing problem for a substantial number of people and, with an aging population, the incidence and severity of hearing loss will become more significant over time. There are very few therapies currently available to treat hearing loss, and so the development of new therapeutic strategies for hearing impaired individuals is of paramount importance to address this unmet clinical need. Most forms of hearing loss are progressive in nature and therefore an opportunity exists to develop novel therapeutic approaches to slow or halt hearing loss progression, or even repair or replace lost hearing function. Numerous emerging technologies have potential as therapeutic options. This paper details the potential of cell- and gene-based therapies to provide therapeutic agents to protect sensory and neural cells from various insults known to cause hearing loss; explores the potential of replacing lost sensory and nerve cells using gene and stem cell therapy; and describes the considerations for clinical translation and the challenges that need to be overcome.

Gillespie, Lisa N.; Richardson, Rachael T.; Nayagam, Bryony A.; Wise, Andrew K.

2014-12-01

266

Roadmap: Radiologic Imaging Sciences Radiation Therapy (Freshman or AS degree) Bachelor of Radiologic Imaging Sciences Technology  

E-print Network

Roadmap: Radiologic Imaging Sciences ­ Radiation Therapy (Freshman or AS degree) ­ Bachelor of Radiologic Imaging Sciences Technology [RE-BRIT-RIS-RTFE] Regional College Catalog Year: 2012-2013 Page 1 Semester Seven (Summer): [2 Credit Hours] RIS 44000 Introduction to Radiologic Imaging Sciences 2 C

Sheridan, Scott

267

The Life Cycle of Images: Revisiting the Ethical Treatment of the Art Therapy Image  

ERIC Educational Resources Information Center

Using the metaphor of the human life cycle, the author of this viewpoint suggests that consideration of the birth, life, and death of images made in art therapy may promote a new perspective on their ethical treatment. A developmental view of images encourages art therapists to see art images as living entities that undergo a natural life cycle.…

Hinz, Lisa D.

2013-01-01

268

Bioelectrical strategies for image-guided therapies  

E-print Network

There is a pressing need in minimally-invasive surgery for novel imaging methods that can rapidly and accurately localize the surgical instrument and its target. We have developed two novel localization methods for the ...

Barley, Maya

2007-01-01

269

Gene therapy for renal anemia in mice with polycystic kidney using an adenovirus vector encoding the human erythropoietin gene  

Microsoft Academic Search

Gene therapy for renal anemia in mice with polycystic kidney using an adenovirus vector encoding the human erythropoietin gene.BackgroundRecombinant human erythropoietin (rHuEPO) is primarily used for patients with anemia associated with end-stage renal disease. We evaluated the efficacy of EPO gene therapy using adenovirus vector for chronic renal failure mice expressing severe renal anemia.MethodsRecombinant HuEPO gene transfer to mesothelial cells

Shiwori Osada; Isao Ebihara; Yasuhiro Setoguchi; Hisahide Takahashi; Yasuhiko Tomino; Hikaru Koide

1999-01-01

270

Achromatopsia as a Potential Candidate for Gene Therapy  

PubMed Central

Achromatopsia is an autosomal recessive retinal disease involving loss of cone function that afflicts approximately 1 in 30,000 individuals. Patients with achromatopsia usually have visual acuities lower than 20/200 because of the central vision loss, photophobia, complete color blindness and reduced cone-mediated electroretinographic (ERG) amplitudes. Mutations in three genes have been found to be the primary causes of achromatopsia, including CNGB3 (beta subunit of the cone cyclic nucleotide-gated cation channel), CNGA3 (alpha subunit of the cone cyclic nucleotide-gated cation channel), and GNAT2 (cone specific alpha subunit of transducin). Naturally occurring mouse models with mutations in Cnga3 (cpfl5 mice) and Gnat2 (cpfl3 mice) were discovered at The Jackson Laboratory. A natural occurring canine model with CNGB3 mutations has also been found. These animal models have many of the central phenotypic features of the corresponding human diseases. Using adeno-associated virus (AAV)-mediated gene therapy, we and others show that cone function can be restored in all three models. These data suggest that human achromatopsia may be a good candidate for corrective gene therapy. PMID:20238068

Pang, Ji-jing; Alexander, John; Lei, Bo; Deng, Wentao; Zhang, Keqing; Li, Qiuhong; Chang, Bo; Hauswirth, William W.

2013-01-01

271

Autologous stem cell transplant with gene therapy for Friedreich ataxia.  

PubMed

We advance the overarching hypothesis that stem cell therapy is a potent treatment for Friedreich's ataxia (FRDA). Here, we discuss the feasibility of autologous transplantation in FRDA, highlighting the need for the successful isolation of the FRDA patient's bone marrow-derived mesenchymal stem cells, followed by characterization that these cells maintain the GAA repeat expansion and the reduced FXN mRNA expression, both hallmark features of FRDA. Next, we discuss the need for assessment of the proliferative capability and pluripotency of FRDA patient's bone marrow-derived mesenchymal stem cells. In particular, we view the need for characterizing the in vitro differentiation of bone marrow-derived mesenchymal stem cells into the two cell types primarily affected in FRDA, peripheral neurons and cardiomyocytes. Finally, we discuss the need to test the application of bone marrow-derived mesenchymal stem cells as potent autologous donor cells for FRDA. The demonstration of the functional correction of the mutated gene in these cells will be a critical endpoint of determining the potential of stem cell therapy in FRDA. We envision a gene-based cell transplant strategy as a likely therapeutic approach for FRDA, involving stable insertion of functional human bacterial artificial chromosomes or BACs containing the intact FXN gene into stem cells, thereafter leading to the expression of frataxin protein in differentiated neurons/cardiomyocytes. PMID:24962209

Tajiri, Naoki; Staples, Meaghan; Kaneko, Yuji; Kim, Seung U; Zesiewicz, Theresa A; Borlongan, Cesar V

2014-09-01

272

Encapsulation of viral vectors for gene therapy applications.  

PubMed

In gene therapy, a number of viruses are currently being used as vectors to provide transient expression of therapeutic proteins. A drawback of using free virus is that it gives a potent immune response, which reduces gene transfer and limits re-administration. An alternative delivery system is to encapsulate the virus in poly(lactide-co-glycolide) (PLG) microspheres prior to administration. A recombinant adenovirus (Ad) expressing green fluorescent protein (GFP) was used to test the transduction efficiency of Ad encapsulated in microspheres on target cells. The number of infected cells that expressed GFP was measured by flow cytometry. It was demonstrated that encapsulated viral vectors could successfully transduce target cells with encapsulation efficiencies up to 23% and that the level of transduction could be controlled by varying both the quantity of microspheres and the amount of Ad in the microspheres. High transduction efficiencies and its recognized biocompatibility make PLG-encapsulated Ad an attractive alternative to the use of free virus in gene therapy applications. The infectivity of Ad was found to be significantly influenced by the processing conditions and changes in environmental factors. Free Ad and encapsulated Ad were able to infect both E1 complimenting cells (HEK 293) and non-complimenting cells (A549), with the viral expression in HEK 293 cells being 2.1 times greater than for A549 cells. PMID:17286384

Turner, Peter; Petch, Amelia; Al-Rubeai, Mohamed

2007-01-01

273

Cationic Polyene Phospholipids as DNA Carriers for Ocular Gene Therapy  

PubMed Central

Recent success in the treatment of congenital blindness demonstrates the potential of ocular gene therapy as a therapeutic approach. The eye is a good target due to its small size, minimal diffusion of therapeutic agent to the systemic circulation, and low immune and inflammatory responses. Currently, most approaches are based on viral vectors, but efforts continue towards the synthesis and evaluation of new nonviral carriers to improve nucleic acid delivery. Our objective is to evaluate the efficiency of novel cationic retinoic and carotenoic glycol phospholipids, designated C20-18, C20-20, and C30-20, to deliver DNA to human retinal pigmented epithelium (RPE) cells. Liposomes were produced by solvent evaporation of ethanolic mixtures of the polyene compounds and coformulated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or cholesterol (Chol). Addition of DNA to the liposomes formed lipoplexes, which were characterized for binding, size, biocompatibility, and transgene efficiency. Lipoplex formulations of suitable size and biocompatibility were assayed for DNA delivery, both qualitatively and quantitatively, using RPE cells and a GFP-encoding plasmid. The retinoic lipoplex formulation with DOPE revealed a transfection efficiency comparable to the known lipid references 3?-[N-(N?,N?-dimethylaminoethane)-carbamoyl]-cholesterol (DC-Chol) and 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EPC) and GeneJuice. The results demonstrate that cationic polyene phospholipids have potential as DNA carriers for ocular gene therapy. PMID:25147812

Machado, Susana; Calado, Sofia; Bitoque, Diogo; Oliveira, Ana Vanessa; Øpstad, Christer L.; Zeeshan, Muhammad; Sliwka, Hans-Richard; Partali, Vassilia; Pungente, Michael D.; Silva, Gabriela A.

2014-01-01

274

Image-Guidance for Stereotactic Body Radiation Therapy  

SciTech Connect

The term stereotactic body radiation therapy (SBRT) describes a recently introduced external beam radiation paradigm by which small lesions outside the brain are treated under stereotactic conditions, in a single or few fractions of high-dose radiation delivery. Similar to the treatment planning and delivery process for cranial radiosurgery, the emphasis is on sparing of adjacent normal tissues through the creation of steep dose gradients. Thus, advanced methods for assuring an accurate relationship between the target volume position and radiation beam geometry, immediately prior to radiation delivery, must be implemented. Such methods can employ imaging techniques such as planar (e.g., x-ray) or volumetric (e.g., computed tomography [CT]) approaches and are commonly summarized under the general term image-guided radiation therapy (IGRT). This review summarizes clinical experience with volumetric and ultrasound based image-guidance for SBRT. Additionally, challenges and potential limitations of pre-treatment image-guidance are presented and discussed.

Fuss, Martin [Department of Radiation Medicine, Oregon Health and Science University, Portland, OR (United States) and Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX (United States) and Cancer Therapy and Research Center, San Antonio, TX (United States)]. E-mail: fussm@ohsu.edu; Boda-Heggemann, Judit [Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Mannheim (Germany); Papanikolau, Nikos [Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX (United States); Cancer Therapy and Research Center, San Antonio, TX (United States); Salter, Bill J. [Department of Radiation Oncology, University of Utah, Salt Lake City, UT (United States); Huntsman Cancer Institute, Salt Lake City, UT (United States)

2007-07-01

275

Extended Survival of Glioblastoma Patients After Chemoprotective HSC Gene Therapy  

PubMed Central

Alkylating agent chemotherapy for malignant disease results in myelosuppression which significantly limits dose-escalation and potential clinical efficacy. Drug resistance gene therapy with mutant MGMT (P140K) gene-modified hematopoietic stem cells may circumvent this problem but has not been evaluated clinically. Here we show efficient, polyclonal engraftment of P140K-modified hematopoietic cells in patients with unmethylated MGMT promoter glioblastomas with apparently normal BM after well-tolerated, nonmyeloablative conditioning with BCNU. Increases in P140K-modified cells after post-transplant chemotherapy including temozolomide and O6-benzylguanine indicate protection and selection of gene-modified hematopoietic repopulating cells. Longitudinal retroviral integration site (RIS) analysis identified over 12,000 unique RIS in the first three patients with multiple clones present in PB of each patient throughout multiple chemotherapy treatments. To assess safety, RIS distribution was monitored over time and chemotherapy treatments. Two patients exhibited emergence of prominent clones harboring RIS associated with the intronic coding region of PRDM16 or the 3? UTR of HMGA2 genes with no adverse clinical outcomes. All three patients surpassed the median survival for patients with unmethlyated MGMT promoter glioblastomas, with one patient alive and progression-free more than two years since diagnosis. We conclude that transplantation of P140K-expressing hematopoietic cells mediates chemoprotection and selection, potentially maximizing chemotherapy administration in the treatment of cancer and providing a strategy for increasing gene-corrected/therapeutic cell levels in patients with genetic or infectious diseases. PMID:22572881

Adair, Jennifer E.; Beard, Brian C.; Trobridge, Grant D.; Neff, Tobias; Rockhill, Jason K.; Silbergeld, Daniel L.; Mrugala, Maciej; Kiem, Hans-Peter

2013-01-01

276

Optoacoustic Imaging for Guiding and Monitoring HIFU Therapy  

NASA Astrophysics Data System (ADS)

Although high-intensity focused ultrasound (HIFU) has exciting potential for noninvasively treating tumors and cardiac diseases, its clinical acceptance is hindered by the lack of a reliable and cost-effective method of noninvasively guiding and monitoring the treatment. The present study investigated the feasibility of employing optoacoustic imaging (OAI) for guiding and monitoring HIFU therapy. OAI combines molecular specificity provided by optical imaging and the resolution provided by diagnostic ultrasound. A 3-D optoacoustic imaging system was used to visualize thermal lesions produced in excised tissue specimens and in vivo mice using high intensity focused ultrasound (HIFU). A 7.5 MHz surgical, focused transducer with a radius of curvature of 35 mm and an aperture of 23 mm generated HIFU. A pulsed laser, which could operate at 755 nm and 1064 nm, illuminated the specimens. Tomographic images were obtained using a 64 element curved array while the specimens were rotated incrementally. Images were acquired before and after HIFU exposure. The images were then combined to reconstruct 3-D volume images (voxel resolution 0.5 mm). Optoacoustic images using 1064-nm illumination provided visualization of HIFU lesions. The location and the extent of the lesions were confirmed upon dissection. These preliminary results demonstrate the potential of optoacoustic imaging to assess and monitor HIFU therapy.

Chitnis, Parag V.; Brecht, Hans P.; Su, Richard; Oraevsky, Alexander A.

2011-09-01

277

Dual-mode transducers for ultrasound imaging and thermal therapy.  

PubMed

Medical imaging is a vital component of high intensity focused ultrasound (HIFU) therapy, which is gaining clinical acceptance for tissue ablation and cancer therapy. Imaging is necessary to plan and guide the application of therapeutic ultrasound, and to monitor the effects it induces in tissue. Because they can transmit high intensity continuous wave ultrasound for treatment and pulsed ultrasound for imaging, dual-mode transducers aim to improve the guidance and monitoring stages. Their primary advantage is implicit registration between the imaging and treatment axes, and so they can help ensure before treatment that the therapeutic beam is correctly aligned with the planned treatment volume. During treatment, imaging signals can be processed in real-time to assess acoustic properties of the tissue that are related to thermal ablation. Piezocomposite materials are favorable for dual-mode transducers because of their improved bandwidth, which in turn improves imaging performance while maintaining high efficiency for treatment. Here we present our experiences with three dual-mode transducers for interstitial applications. The first was an 11-MHz monoelement designed for use in the bile duct. It had a 25x7.5 mm(2) aperture that was cylindrically focused to 10mm. The applicator motion was step-wise rotational for imaging and therapy over a 360 degrees, or smaller, sector. The second transducer had 5-elements, each measuring 3.0x3.8 mm(2) for a total aperture of 3.0x20 mm(2). It operated at 5.6 MHz, was cylindrically focused to 14 mm, and was integrated with a servo-controlled oscillating probe designed for sector imaging and directive therapy in the liver. The last transducer was a 5-MHz, 64-element linear array designed for beam-formed imaging and therapy. The aperture was 3.0x18 mm(2) with a pitch of 0.280 mm. Characterization results included conversion efficiencies above 50%, pulse-echo bandwidths above 50%, surface intensities up to 30 W/cm(2), and axial imaging resolutions to 0.2 mm. The second transducer was evaluated in vivo using porcine liver, where coagulation necrosis was induced up to a depth of 20 mm in 120 s. B-mode and M-mode images displayed a hypoechoic region that agreed well with lesion depth observed by gross histology. These feasibility studies demonstrate that the dual-mode transducers had imaging performance that was sufficient to aid the guidance and monitoring of treatment, and could sustain high intensities to induce coagulation necrosis in vivo. PMID:19758673

Owen, N R; Chapelon, J Y; Bouchoux, G; Berriet, R; Fleury, G; Lafon, C

2010-02-01

278

Gene Therapy (2000) 7, 12741283 2000 Macmillan Publishers Ltd All rights reserved 0969-7128/00 $15.00  

E-print Network

Gene Therapy (2000) 7, 1274­1283 © 2000 Macmillan Publishers Ltd All rights reserved 0969 vectors for study of cytochrome P450 gene regulation, as well as for liver-directed gene therapy in humans. Gene Therapy (2000) 7, 1274­1283. polyhedrosis virus) vectors can be used to shuttle foreign genes

Omiecinski, Curtis

279

Imaging and Tumor Localization for Ion Beam Therapy  

NASA Astrophysics Data System (ADS)

Ion beam therapy (IBT) requires an increased degree of precision in patient positioning, treatment planning, and monitoring in order to exploit the full potential of this treatment modality. This chapter discusses aspects of imaging for treatment planning and treatment set-up that are specific for this form of high precision radiotherapy. Special considerations about functional imaging, which are connected to the radiobiological properties of heavier ions, are also highlighted.

Jäkel, Oliver

280

In Vivo Surgical Resection Plus Adjuvant Gene Therapy in the Treatment of Mammary and Prostate Cancer  

Microsoft Academic Search

Adenoviral-mediated gene therapy delivery, combining the herpes simplex virus thymidine kinase gene (Ad-tk) with gancyclovir, has been evaluated as a treatment modality for numerous tumors in the laboratory and in the clinics. As a single modality, gene therapy has shown some promising local and systemic results but no curative success. Surgery is the standard of care for many solid tumors.

Steven W. Sukin; Madhu Chhikara; Xiaohong Zhu; Gustavo Ayala; Laura K. Aguilar; E. O'Brian Smith; Brian J. Miles; Timothy C. Thompson; Dov Kadmon; Estuardo Aguilar-Cordova

2001-01-01

281

Hum Gene Ther . Author manuscript Developing cell therapy techniques for respiratory disease: intratracheal  

E-print Network

Hum Gene Ther . Author manuscript Page /1 15 Developing cell therapy techniques for respiratory, in a murine model of acute epithelial airway injury already used in gene therapy experiments on cystic repair and serve as carriers of a therapeutic gene for genetic airway disease such as cystic fibrosis. We

Paris-Sud XI, Université de

282

Cellular Immunity to Viral Antigens Limits E1-Deleted Adenoviruses for Gene Therapy  

Microsoft Academic Search

An important limitation that has emerged in the use of adenoviruses for gene therapy has been loss of recombinant gene expression that occurs concurrent with the development of pathology in the organ expressing the transgene. We have used liver-directed approaches to gene therapy in mice to study mechanisms that underlie the problems with transient expression and pathology that have characterized

Yiping Yang; Frederick A. Nunes; Klara Berencsi; Emma E. Furth; Eva Gonczol; James M. Wilson

1994-01-01

283

Promises of gene therapy, Mario CapecchiSite: DNA Interactive (www.dnai.org)  

NSDL National Science Digital Library

Interviewee: Mario Capecchi DNAi Location: Applications>Genes and Medicine>Gene targeting>Possibilities Possibilities for new therapies Mario Capecchi talks about the possible use of embryonic stem cells and gene targeting techniques to develop new therapies for for diabetes and Parkinson's.

2008-03-26

284

Delivery and Protection of Adenoviruses Using Biocompatible Hydrogels for Localized Gene Therapy  

Microsoft Academic Search

Localized gene delivery for repair of bone defects requires appropriate carriers for the gene therapy vectors. The objective of this study was to determine if hydrogels can control temporal and spatial delivery of adenovirus for localized gene therapy. Adenovirus expressing ?-galactosidase was suspended in liquid or fibrin or collagen gels of varied concentrations and incubated prior to testing its bioactivity.

Rachel Maddox Schek; Scott J. Hollister; Paul H. Krebsbach

2004-01-01

285

Tissue-Engineered Skeletal Muscle Organoids for Reversible Gene Therapy  

NASA Technical Reports Server (NTRS)

Genetically modified murine skeletal myoblasts were tissue engineered in vitro into organ-like structures (organoids) containing only postmitotic myoribers secreting pharmacological levels of recombinant human growth hormone (rhGH). Subcutaneous organoid implantation under tension led to the rapid and stable appearance of physiological sera levels of rhGH for up to 12 weeks, whereas surgical removal led to its rapid disappearance. Reversible delivery of bioactive compounds from postmitotic cells in tissue engineered organs has several advantages over other forms of muscle gene therapy.

Vandenburgh, Herman; DelTatto, Michael; Shansky, Janet; Lemaire, Julie; Chang, Albert; Payumo, Francis; Lee, Peter; Goodyear, Amy; Raven, Latasha

1996-01-01

286

Tissue-Engineered Skeletal Muscle Organoids for Reversible Gene Therapy  

NASA Technical Reports Server (NTRS)

Genetically modified murine skeletal myoblasts were tissue engineered in vitro into organ-like structures (organoids) containing only postmitotic myofibers secreting pharmacological levels of recombinant human growth hormone (rhGH). Subcutaneous organoid Implantation under tension led to the rapid and stable appearance of physiological sera levels of rhGH for up to 12 weeks, whereas surgical removal led to its rapid disappearance. Reversible delivery of bioactive compounds from postimtotic cells in tissue engineered organs has several advantages over other forms of muscle gene therapy.

Vandenburgh, Herman; DelTatto, Michael; Shansky, Janet; Lemaire, Julie; Chang, Albert; Payumo, Francis; Lee, Peter; Goodyear, Amy; Raven, Latasha

1996-01-01

287

A clinical trial of gene therapy for chronic pain  

PubMed Central

The first human trial of gene therapy for chronic pain, a phase 1 study of a non-replicating herpes simplex virus (HSV)-based vector engineered to express preproenkephalin in patients with intractable pain from cancer, began enrolling subjects in December 2008. In this article we describe the rationale underlying this potential approach to treatment of pain, the preclinical animal data in support of this approach, the design of the study, and studies with additional HSV-based vectors that may be used to develop treatment for other types of pain. PMID:19818042

Wolfe, Darren; Wechuck, James; Krisky, David; Mata, Marina; Fink, David J.

2011-01-01

288

Long-term follow-up after gene therapy for canavan disease.  

PubMed

Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 10(11) vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status. PMID:23253610

Leone, Paola; Shera, David; McPhee, Scott W J; Francis, Jeremy S; Kolodny, Edwin H; Bilaniuk, Larissa T; Wang, Dah-Jyuu; Assadi, Mitra; Goldfarb, Olga; Goldman, H Warren; Freese, Andrew; Young, Deborah; During, Matthew J; Samulski, R Jude; Janson, Christopher G

2012-12-19

289

Long-Term Follow-Up After Gene Therapy for Canavan Disease  

PubMed Central

Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetylaspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 1011 vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status. PMID:23253610

Leone, Paola; Shera, David; McPhee, Scott W.J.; Francis, Jeremy S.; Kolodny, Edwin H.; Bilaniuk, Larissa T.; Wang, Dah-Jyuu; Assadi, Mitra; Goldfarb, Olga; Goldman, H. Warren; Freese, Andrew; Young, Deborah; During, Matthew J.; Samulski, R. Jude; Janson, Christopher G.

2013-01-01

290

Combination gene therapy for liver metastasis of colon carcinoma in vivo.  

PubMed Central

The efficacy of combination therapy with a "suicide gene" and a cytokine gene to treat metastatic colon carcinoma in the liver was investigated. Tumor in the liver was generated by intrahepatic injection of a colon carcinoma cell line (MCA-26) in syngeneic BALB/c mice. Recombinant adenoviral vectors containing various control and therapeutic genes were injected directly into the solid tumors, followed by treatment with ganciclovir. While the tumors continued to grow in all animals treated with a control vector or a mouse interleukin 2 vector, those treated with a herpes simplex virus thymidine kinase vector, with or without the coadministration of the mouse interleukin 2 vector, exhibited dramatic necrosis and regression. However, only animals treated with both vectors developed an effective systemic antitumoral immunity against challenges of tumorigenic doses of parental tumor cells inoculated at distant sites. The antitumoral immunity was associated with the presence of MCA-26 tumor-specific cytolytic CD8+ T lymphocytes. The results suggest that combination suicide and cytokine gene therapy in vivo can be a powerful approach for treatment of metastatic colon carcinoma in the liver. Images Fig. 2 PMID:7708688

Chen, S H; Chen, X H; Wang, Y; Kosai, K; Finegold, M J; Rich, S S; Woo, S L

1995-01-01

291

A non-invasive tissue-specific molecular delivery method of cancer gene therapy.  

PubMed

A Japanese word, monozukuri (literally translated "making things") is the philosophy of first having the idea and then the faith in the technical expertise and experience to accomplish the result. We believe that the concept of engineering is monozukuri. Through the process of monozukuri, engineered natural science based on mathematics and physics has been developed. Medicine is the field of study which has been developed for maintaining daily healthy life with diagnosis, treatment, examination, and protection. Biomedical engineering is the interdisciplinary study of engineering and medicine, and should be developed based on monozukuri. In this particular research, we have developed a physical molecular delivery method for cancer gene therapy using nano/microbubbles and ultrasound. First, the behavior of cavitation bubbles and subsequent shock wave phenomena involved in the mechanism of molecular delivery were analyzed, combining theory and computer simulation. In a second step, the methodology was optimized in vitro and in vivo. Finally, the therapeutic potential of the method in pre-clinical models was evaluated using transgenes relevant to cancer gene therapy instead of reporter genes, and whole body, non-invasive imaging using single photon emission computed tomography (SPECT/CT) was used to evaluate the selectivity of gene delivery in vivo. PMID:16966136

Kodama, Tetsuya; Aoi, Atsuko; Vassaux, Georges; Mori, Shiro; Morikawa, Hidehiro; Koshiyama, Keni-Chiro; Yano, Takeru; Fujikawa, Shigeo; Tomita, Yukio

2006-01-01

292

Quantitative analysis of non-viral gene therapy in primary liver culture systems  

E-print Network

Gene therapy has the potential to cure thousands of diseases caused by genetic abnormalities, provide novel combination therapies for cancers and viral infections, and offer a new and effective platform for next generation ...

Tedford, Nathan C

2007-01-01

293

Image-guided interventional therapy for cancer with radiotherapeutic nanoparticles.  

PubMed

One of the major limitations of current cancer therapy is the inability to deliver tumoricidal agents throughout the entire tumor mass using traditional intravenous administration. Nanoparticles carrying beta-emitting therapeutic radionuclides that are delivered using advanced image-guidance have significant potential to improve solid tumor therapy. The use of image-guidance in combination with nanoparticle carriers can improve the delivery of localized radiation to tumors. Nanoparticles labeled with certain beta-emitting radionuclides are intrinsically theranostic agents that can provide information regarding distribution and regional dosimetry within the tumor and the body. Image-guided thermal therapy results in increased uptake of intravenous nanoparticles within tumors, improving therapy. In addition, nanoparticles are ideal carriers for direct intratumoral infusion of beta-emitting radionuclides by convection enhanced delivery, permitting the delivery of localized therapeutic radiation without the requirement of the radionuclide exiting from the nanoparticle. With this approach, very high doses of radiation can be delivered to solid tumors while sparing normal organs. Recent technological developments in image-guidance, convection enhanced delivery and newly developed nanoparticles carrying beta-emitting radionuclides will be reviewed. Examples will be shown describing how this new approach has promise for the treatment of brain, head and neck, and other types of solid tumors. PMID:25016083

Phillips, William T; Bao, Ande; Brenner, Andrew J; Goins, Beth A

2014-09-30

294

Physics in Modern Medicine: Applications in Imaging, Surgery, and Therapy  

NSDL National Science Digital Library

This is the website for a course on medical technologies and the physical principles behind them for non-scientists. Topics covered include laparoscopic and laser surgery, photodynamic therapy, and a range of imaging techniques. Included on this page is the course syllabus and a list of internet resources that will be useful to help students research projects.

Kane, Suzanne A.

2009-10-26

295

[Development of bifunctional radiopharmaceuticals for targeted imaging and therapy].  

PubMed

In vivo radiopharmaceuticals have two different uses - for nuclear diagnostic imaging and for internal radiation therapy. For nuclear diagnostic imaging, it is necessary to make the difference of radioactivity levels between in the target regions and in the other regions at an early time after administration. For internal radiation therapy, a more selective accumulation of the radioactivity to the target regions is required to minimize an adverse effect. In order to achieve the highly selective accumulation of in vivo radiopharmaceuticals, it is necessary to find an appropriate target molecule in the first place and design a compound which can recognize the target molecule and stably label it with radionuclide. There are several proposed approaches to chemical design for this purpose. However, even with the specific recognition and stable radiolabel, targeted imaging and therapy are not necessarily achieved. We have been developing in vivo radiopharmaceuticals based on a chemical design called "bifunctional radiopharmaceutical." Bifunctional radiopharmaceuticals have the recognition site of the target molecule and binding site for the radionuclide independently in one molecule. This review summarizes our examples of chemical design of in vivo radiopharmaceuticals to achieve the targeted imaging and therapy. PMID:18057782

Mukai, Takahiro

2007-12-01

296

Clinical development of gene therapy needs a tailored approach: a regulatory perspective from the European Union.  

PubMed

Gene therapy is a rapidly evolving field that needs an integrated approach, as acknowledged in the concept article on the revision of the guideline on gene transfer medicinal products. The first gene therapy application for marketing authorization was approved in the International Conference on Harmonisation (ICH) region in 2012, the product being Alipogene tiparvovec. The regulatory process for this product has been commented on extensively, highlighting the challenges posed by such a novel technology. Here, as current or previous members of the Committee for Advanced Therapies, we share our perspectives and views on gene therapy as a treatment modality based on current common understanding and regulatory experience of gene therapy products in the European Union to date. It is our view that a tailored approach is needed for a given gene therapy product in order to achieve successful marketing authorization. PMID:24649836

Narayanan, Gopalan; Cossu, Giulio; Galli, Maria Cristina; Flory, Egbert; Ovelgonne, Hans; Salmikangas, Paula; Schneider, Christian K; Trouvin, Jean-Hugues

2014-03-01

297

Gene Therapy in Large Animal Models of Muscular Dystrophy  

PubMed Central

The muscular dystrophies are a group of genetically and phenotypically heterogeneously inherited diseases characterized by progressive muscle wasting, which can lead to premature death in severe forms such as Duchenne muscular dystrophy (DMD). In many cases they are caused by the absence of proteins that are critical components of the dystrophin-glycoprotein complex, which links the cytoskeleton and the basal lamina. There is no effective treatment for these disorders at present, but several novel strategies for replacing or repairing the defective gene are in development, with early encouraging results from animal models. We review these strategies, which include the use of stem cells of different tissue origins, gene replacement therapies mediated by various viral vectors, and transcript repair treatments using exon skipping strategies. We comment on their advantages and on limitations that must be overcome before successful application to human patients. Our focus is on studies in a clinically relevant large canine model of DMD. Recent advances in the field suggest that effective therapies for muscular dystrophies are on the horizon. Because of the complex nature of these diseases, it may be necessary to combine multiple approaches to achieve a successful treatment. PMID:19293461

Wang, Zejing; Chamberlain, Jeffrey S.; Tapscott, Stephen J.; Storb, Rainer

2009-01-01

298

Physiologic and metabolic safety of butyrylcholinesterase gene therapy in mice.  

PubMed

In continuing efforts to develop gene transfer of human butyrylcholinesterase (BChE) as therapy for cocaine addiction, we conducted wide-ranging studies of physiological and metabolic safety. For that purpose, mice were given injections of adeno-associated virus (AAV) vector or helper-dependent adenoviral (hdAD) vector encoding human or mouse BChE mutated for optimal cocaine hydrolysis. Age-matched controls received saline or AAV-luciferase control vector. At times when transduced BChE was abundant, physiologic and metabolic parameters in conscious animals were evaluated by non-invasive Echo-MRI and an automated "Comprehensive Laboratory Animal Monitoring System" (CLAMS). Despite high vector doses (up to 10(13) particles per mouse) and high levels of transgene protein in the plasma (?1500-fold above baseline), the CLAMS apparatus revealed no adverse physiologic or metabolic effects. Likewise, body composition determined by Echo-MRI, and glucose tolerance remained normal. A CLAMS study of vector-treated mice given 40 mg/kg cocaine showed none of the physiologic and metabolic fluctuations exhibited in controls. We conclude that neither the tested vectors nor great excesses of circulating BChE affect general physiology directly, while they protect mice from disturbance by cocaine. Hence, viral gene transfer of BChE appears benign and worth exploring as a therapy for cocaine abuse and possibly other disorders as well. PMID:24892251

Murthy, Vishakantha; Gao, Yang; Geng, Liyi; LeBrasseur, Nathan K; White, Thomas A; Parks, Robin J; Brimijoin, Stephen

2014-07-16

299

Gene therapy for the neurological manifestations in lysosomal storage disorders.  

PubMed

Over the past several years, considerable progress has been made in the development of gene therapy as a therapeutic strategy for a variety of inherited metabolic diseases, including neuropathic lysosomal storage disorders (LSDs). The premise of gene therapy for this group of diseases is borne of findings that genetic modification of a subset of cells can provide a more global benefit by virtue of the ability of the secreted lysosomal enzymes to effect cross-correction of adjacent and distal cells. Preclinical studies in small and large animal models of these disorders support the application of either a direct in vivo approach using recombinant adeno-associated viral vectors or an ex vivo strategy using lentiviral vector-modified hematopoietic stem cells to correct the neurological component of these diseases. Early clinical studies utilizing both approaches have begun or are in late-stage planning for a small number of neuropathic LSDs. Although initial indications from these studies are encouraging, it is evident that second-generation vectors that exhibit a greater safety profile and transduction activity may be required before this optimism can be fully realized. Here, I review recent progress and the remaining challenges to treat the neurological aspects of various LSDs using this therapeutic paradigm. PMID:24683200

Cheng, Seng H

2014-09-01

300

Single doublecortin gene therapy significantly reduces glioma tumor volume  

PubMed Central

We employed lentivirus based doublecortin (DCX), as a glioma suppressor gene therapy in an intracranial glioma tumor xenograft model in nude rats. Single DCX expressing lentivirus was directly administered into the tumor on day 8 after U87 tumor cell implantation. DCX treatment significantly reduced U87 glioma tumor volume (~60%) on day 14 after DCX lentivirus injection and significantly improved median survival of tumor bearing nude rats. DCX synthesis induced neuronal markers MAP2, TUJ1 and PSA-NCAM, and the glial marker, glial fibrillary acidic protein (GFAP) in the implanted U87 glioma tumors. DCX synthesis induced GFAP that co-localized with tubulin in the mitotic stage, inhibited cleavage furrow during cytokinesis and blocked mitosis in glioma cells. DCX lentivirus infection did not induce apoptosis, but significantly inhibited expression of the proliferation marker Ki-67 and the blood vessel marker von-Willebrand Factor (vWF). U87 and other glioma cells except brain tumor stem cells (BTSCs) do not express neuronal markers or both neuronal and glial markers. DCX synthesizing glioma cells express a phenotype of anti-angiogenic BTSC-like cells with terminal differentiation that causes remission of glioma cells by blocking mitosis via a novel DCX/GFAP pathway. Direct local delivery of lentivirus based DCX gene therapy is a potential differentiation based therapeutic approach for the treatment of glioma. PMID:19681167

Santra, Manoranjan; Zheng, Xuguang; Roberts, Cindi; Santra, Sutapa; Lu, Mei; Panda, Swayamprava; Jiang, Feng; Chopp, Michael

2009-01-01

301

Systematic measurements of whole-body imaging dose distributions in image-guided radiation therapy  

SciTech Connect

Purpose: The full benefit of the increased precision of contemporary treatment techniques can only be exploited if the accuracy of the patient positioning is guaranteed. Therefore, more and more imaging modalities are used in the process of the patient setup in clinical routine of radiation therapy. The improved accuracy in patient positioning, however, results in additional dose contributions to the integral patient dose. To quantify this, absorbed dose measurements from typical imaging procedures involved in an image-guided radiation therapy treatment were measured in an anthropomorphic phantom for a complete course of treatment. The experimental setup, including the measurement positions in the phantom, was exactly the same as in a preceding study of radiotherapy stray dose measurements. This allows a direct combination of imaging dose distributions with the therapy dose distribution. Methods: Individually calibrated thermoluminescent dosimeters were used to measure absorbed dose in an anthropomorphic phantom at 184 locations. The dose distributions from imaging devices used with treatment machines from the manufacturers Accuray, Elekta, Siemens, and Varian and from computed tomography scanners from GE Healthcare were determined and the resulting effective dose was calculated. The list of investigated imaging techniques consisted of cone beam computed tomography (kilo- and megavoltage), megavoltage fan beam computed tomography, kilo- and megavoltage planar imaging, planning computed tomography with and without gating methods and planar scout views. Results: A conventional 3D planning CT resulted in an effective dose additional to the treatment stray dose of less than 1 mSv outside of the treated volume, whereas a 4D planning CT resulted in a 10 times larger dose. For a daily setup of the patient with two planar kilovoltage images or with a fan beam CT at the TomoTherapy unit, an additional effective dose outside of the treated volume of less than 0.4 mSv and 1.4 mSv was measured, respectively. Using kilovoltage or megavoltage radiation to obtain cone beam computed tomography scans led to an additional dose of 8-46 mSv. For treatment verification images performed once per week using double exposure technique, an additional effective dose of up to 18 mSv was measured. Conclusions: Daily setup imaging using kilovoltage planar images or TomoTherapy megavoltage fan beam CT imaging can be used as a standard procedure in clinical routine. Daily kilovoltage and megavoltage cone beam computed tomography setup imaging should be applied on an individual or indication based protocol. Depending on the imaging scheme applied, image-guided radiation therapy can be administered without increasing the dose outside of the treated volume compared to therapies without image guidance.

Haelg, Roger A.; Besserer, Juergen; Schneider, Uwe [Radiotherapie Hirslanden AG, Institute for Radiotherapy, Aarau 5000 (Switzerland); Vetsuisse Faculty, University of Zurich, Zurich 8057 (Switzerland) and Radiotherapie Hirslanden AG, Institute for Radiotherapy, Aarau 5000 (Switzerland)

2012-12-15

302

Molecular Imaging in Traditional Chinese Medicine Therapy for Neurological Diseases  

PubMed Central

With the speeding tendency of aging society, human neurological disorders have posed an ever increasing threat to public health care. Human neurological diseases include ischemic brain injury, Alzheimer's disease, Parkinson's disease, and spinal cord injury, which are induced by impairment or specific degeneration of different types of neurons in central nervous system. Currently, there are no more effective treatments against these diseases. Traditional Chinese medicine (TCM) is focused on, which can provide new strategies for the therapy in neurological disorders. TCM, including Chinese herb medicine, acupuncture, and other nonmedication therapies, has its unique therapies in treating neurological diseases. In order to improve the treatment of these disorders by optimizing strategies using TCM and evaluate the therapeutic effects, we have summarized molecular imaging, a new promising technology, to assess noninvasively disease specific in cellular and molecular levels of living models in vivo, that was applied in TCM therapy for neurological diseases. In this review, we mainly focus on applying diverse molecular imaging methodologies in different TCM therapies and monitoring neurological disease, and unveiling the mysteries of TCM. PMID:24222911

Wan, Haitong; Li, Jinhui; Zhang, Hong; Tian, Mei

2013-01-01

303

Gene transfer in human vestibular epithelia and the prospects for inner ear gene therapy.  

PubMed

Transfer of exogenous genetic material into the mammalian inner ear using viral vectors has been characterized over the last decade. A number of different viral vectors have been shown to transfect the varying cell types of the nonprimate mammalian inner ear. Several routes of delivery have been identified for introduction of vectors into the inner ear while minimizing injury to existing structures and at the same time ensuring widespread distribution of the agent throughout the cochlea and the rest of the inner ear. These studies raise the possibility that gene transfer may be developed as a potential strategy for treating inner ear dysfunction in humans. Furthermore, a recent report showing successful transfection of excised human vestibular epithelia offers proof of principle that viral gene transfer is a viable strategy for introduction and expression of exogenous genetic material to restore function to the inner ear. Human vestibular epithelia were harvested from patients undergoing labyrinthectomy, either for intractable Ménière's disease or vestibular schwannoma resection, and cultured for as long as 5 days. In those experiments, recombinant, multiply-deleted, replication-deficient adenoviral vectors were used to transfect and express a reporter gene as well as the functionally relevant gene, wild-type KCNQ4, a potassium channel gene that when mutated causes the autosomal dominant HL DFNA2.Here, we review the current state of viral-mediated gene transfer in the inner ear and discuss different viral vectors, routes of delivery, and potential applications of gene therapy. Emphasis is placed on experiments demonstrating viral transfection of human inner ear tissue and implications of these findings and for the future of gene therapy in the human inner ear. PMID:18300702

Kesser, Bradley W; Hashisaki, George T; Holt, Jeffrey R

2008-05-01

304

Gene Transfer in Human Vestibular Epithelia and the Prospects for Inner Ear Gene Therapy  

PubMed Central

Transfer of exogenous genetic material into the mammalian inner ear using viral vectors has been characterized over the last decade. A number of different viral vectors have been shown to transfect the varying cell types of the nonprimate mammalian inner ear. Several routes of delivery have been identified for introduction of vectors into the inner ear while minimizing injury to existing structures and at the same time ensuring widespread distribution of the agent throughout the cochlea and the rest of the inner ear. These studies raise the possibility that gene transfer may be developed as a potential strategy for treating inner ear dysfunction in humans. Furthermore, a recent report showing successful transfection of excised human vestibular epithelia offers proof of principle that viral gene transfer is a viable strategy for introduction and expression of exogenous genetic material to restore function to the inner ear. Human vestibular epithelia were harvested from patients undergoing labyrinthectomy, either for intractable Ménière’s disease or vestibular schwannoma resection, and cultured for as long as 5 days. In those experiments, recombinant, multiply-deleted, replication-deficient adenoviral vectors were used to transfect and express a reporter gene as well as the functionally relevant gene, wild-type KCNQ4, a potassium channel gene that when mutated causes the autosomal dominant HL DFNA2. Here, we review the current state of viral-mediated gene transfer in the inner ear and discuss different viral vectors, routes of delivery, and potential applications of gene therapy. Emphasis is placed on experiments demonstrating viral transfection of human inner ear tissue and implications of these findings and for the future of gene therapy in the human inner ear. PMID:18300702

Kesser, Bradley W.; Hashisaki, George T.; Holt, Jeffrey R.

2009-01-01

305

Adenovirus Vector-Mediated Gene Transfer into Human Epileptogenic Brain Slices: Prospects for Gene Therapy in Epilepsy  

Microsoft Academic Search

As a first step in the development of a gene therapy approach to epilepsy, we evaluated the ability of adenovirus vectors to direct the transfer into and expression of a marker gene in human brain slices obtained from patients undergoing surgery for medically intractable epilepsy. Following injection of adenovirus vectors containing theEscherichia colilacZ gene into hippocampal and cortical brain slices,

William M. O'Connor; Beverly L. Davidson; Michael G. Kaplitt; Maureen V. Abbey; Paola Leone; David Langer; Michael J. O'Connor; Andrew Freese

1997-01-01

306

HUMAN GENE THERAPY 19:12611271 (November 2008) Mary Ann Liebert, Inc.  

E-print Network

HUMAN GENE THERAPY 19:1261­1271 (November 2008) © Mary Ann Liebert, Inc. DOI: 10.1089/hum.2008.060 Efficiency of High- and Low-Voltage Pulse Combinations for Gene Electrotransfer in Muscle, Liver, Tumor Gene electrotransfer is gaining momentum as an efficient methodology for nonviral gene transfer

Paris-Sud XI, Université de

307

An in vitro nucleoside analog screening method for cancer gene therapy  

Microsoft Academic Search

Suicide genes that sensitize cells to drugs that are normally nontoxic at therapeutic levels represent an important approach in human gene therapy research. We have developed an in vitro screening assay to assess the modulation of nucleoside analogs after transfection of a vector expressing the herpes simplex virus thymidine kinase gene (HSV-TK). The thymidine kinase gene enhances nucleoside phosphorylation to

A. Evrard; L. Vian; C. Aubert; J. P. Cano

1996-01-01

308

Gene therapy in glaucoma-part 2: Genetic etiology and gene mapping  

PubMed Central

Glaucoma diagnosis, identification of people at risk, initiation of treatment and timing of surgical intervention remains a problem. Despite new and improving diagnostic and therapeutic options for glaucoma, blindness from glaucoma is increasing and glaucoma remains a major public health problem. The role of heredity in ocular disease is attracting greater attention as the knowledge and recent advances of Human Genome Project and the HapMap Project have made genetic analysis of many human disorders possible. Glaucoma offers a variety of potential targets for gene therapy. All risk factors for glaucoma and their underlying causes are potentially susceptible to modulation by gene transfer. The discovery of genes responsible for glaucoma has led to the development of new methods of Deoxyribonucleic acid (DNA)-based diagnosis and treatment. As genetic defects responsible for glaucoma are identified and the biochemical mechanisms underlying the disease are recognized, new methods of therapy can be developed. It is of utmost importance for the ophthalmologists and glaucoma specialists to be familiar with and understand the basic molecular mechanisms, genes responsible for glaucoma and the ways of genetic treatment. Method of Literature Search The literature was searched on the Medline database, using the PubMed interface. PMID:21217896

Mahdy, Mohamed Abdel-Monem Soliman

2010-01-01

309

A Novel Linear Accelerator For Image Guided Radiation Therapy  

SciTech Connect

RadiaBeam is developing a novel linear accelerator which produces both kilovoltage ({approx}100 keV) X-rays for imaging, and megavoltage (6 to 20 MeV) X-rays for therapy. We call this system the DEXITron: Dual Energy X-ray source for Imaging and Therapy. The Dexitron is enabled by an innovation in the electromagnetic design of the linac, which allows the output energy to be rapidly switched from high energy to low energy. In brief, the method involves switching the phase of the radiofrequency (RF) power by 180 degrees at some point in the linac such that, after that point, the linac decelerates the beam, rather than accelerating it. The Dexitron will have comparable cost to other linacs, and avoids the problems associated with current IGRT equipment.

Ding Xiaodong; Boucher, Salime [RadiaBeam Technologies, 1717 Stewart St., Santa Monica, CA 90404 (United States)

2011-06-01

310

Functionalized Gold Nanorods for Tumor Imaging and Targeted Therapy  

PubMed Central

Gold nanorods, as an emerging noble metal nanomaterial with unique properties, have become the new exciting focus of theoretical and experimental studies in the past few years. The structure and function of gold nanorods, especially their biocompatibility, optical property, and photothermal effects, have been attracting more and more attention. Gold nanorods exhibit great potential in applications such as tumor molecular imaging and photothermal therapy. In this article, we review some of the main advances made over the past few years in the application of gold nanorods in surface functionalization, molecular imaging, and photothermal therapy. We also explore other prospective applications and discuss the corresponding concepts, issues, approaches, and challenges, with the aim of stimulating broader interest in gold nanorod-based nanotechnology and improving its practical application. PMID:23691482

Gui, Chen; Cui, Da-xiang

2012-01-01

311

Improved Cancer Therapy and Molecular Imaging with Multivalent, Multispecific Antibodies  

PubMed Central

Summation Antibodies are highly versatile proteins with the ability to be used to target diverse compounds, such as radionuclides for imaging and therapy, or drugs and toxins for therapy, but also can be used unconjugated to elicit therapeutically beneficial responses, usually with minimal toxicity. This update describes a new procedure for forming multivalent and/or multispecific proteins, known as the dock-and-lock (DNL) technique. Developed as a procedure for preparing bispecific antibodies capable of binding divalently to a tumor antigen and monovalently to a radiolabeled hapten-peptide for pretargeted imaging and therapy, this methodology has the flexibility to create a number of other biologic agents of therapeutic interest. A variety of constructs, based on anti-CD20 and CD22 antibodies, have been made, with results showing that multispecific antibodies have very different properties from the respective parental monospecific antibodies. The technique is not restricted to antibody combination, but other biologics, such as interferon-?2b, have been prepared. These types of constructs not only allow small biologics to be sustained in the blood longer, but also to be selectively targeted. Thus, DNL technology is a highly flexible platform that can be used to prepare many different types of agents that could further improve cancer detection and therapy. PMID:20187791

Rossi, Edmund A.; Chang, Chien-Hsing; Goldenberg, David M.

2010-01-01

312

Improved cancer therapy and molecular imaging with multivalent, multispecific antibodies.  

PubMed

Antibodies are highly versatile proteins with the ability to be used to target diverse compounds, such as radionuclides for imaging and therapy, or drugs and toxins for therapy, but also can be used unconjugated to elicit therapeutically beneficial responses, usually with minimal toxicity. This update describes a new procedure for forming multivalent and/or multispecific proteins, known as the dock-and-lock (DNL) technique. Developed as a procedure for preparing bispecific antibodies capable of binding divalently to a tumor antigen and monovalently to a radiolabeled hapten-peptide for pretargeted imaging and therapy, this methodology has the flexibility to create a number of other biologic agents of therapeutic interest. A variety of constructs, based on anti-CD20 and CD22 antibodies, have been made, with results showing that multispecific antibodies have very different properties from the respective parental monospecific antibodies. The technique is not restricted to antibody combination, but other biologics, such as interferon-alpha2b, have been prepared. These types of constructs not only allow small biologics to be sustained in the blood longer, but also to be selectively targeted. Thus, DNL technology is a highly flexible platform that can be used to prepare many different types of agents that could further improve cancer detection and therapy. PMID:20187791

Sharkey, Robert M; Rossi, Edmund A; Chang, Chien-Hsing; Goldenberg, David M

2010-02-01

313

Targeted Imaging and Therapy of Brain Cancer using Theranostic Nanoparticles  

PubMed Central

The past decade has seen momentous development in brain cancer research in terms of novel imaging-assisted surgeries, molecularly targeted drug-based treatment regimens or adjuvant therapies and in our understanding of molecular footprints of initiation and progression of malignancy. However, mortality due to brain cancer has essentially remained unchanged in the last three decades. Thus, paradigm-changing diagnostic and therapeutic reagents are urgently needed. Nanotheranostic platforms are powerful tools for imaging and treatment of cancer. Multifunctionality of these nanovehicles offers a number of advantages over conventional agents. These include targeting to a diseased site thereby minimizing systemic toxicity, the ability to solubilize hydrophobic or labile drugs leading to improved pharmacokinetics and their potential to image, treat and predict therapeutic response. In this article, we will discuss the application of newer theranostic nanoparticles in targeted brain cancer imaging and treatment. PMID:20964352

Bhojani, Mahaveer Swaroop; Van Dort, Marcian; Rehemtulla, Alnawaz; Ross, Brian D.

2012-01-01

314

MR imaging of therapy-induced changes of bone marrow  

PubMed Central

MR imaging of bone marrow infiltration by hematologic malignancies provides non-invasive assays of bone marrow cellularity and vascularity to supplement the information provided by bone marrow biopsies. This article will review the MR imaging findings of bone marrow infiltration by hematologic malignancies with special focus on treatment effects. MR imaging findings of the bone marrow after radiation therapy and chemotherapy will be described. In addition, changes in bone marrow microcirculation and metabolism after anti-angiogenesis treatment will be reviewed. Finally, new specific imaging techniques for the depiction of regulatory events that control blood vessel growth and cell proliferation will be discussed. Future developments are directed to yield comprehensive information about bone marrow structure, function and microenvironment. PMID:17021706

Henning, Tobias; Link, Thomas M.

2006-01-01

315

Targeted genome editing tools for disease modeling and gene therapy.  

PubMed

The development of custom-designed nucleases (CDNs), including zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), has made it possible to perform precise genetic engineering in many cell types and species. More recently, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system has been successfully employed for genome editing. These RNA-guided DNA endonucleases are shown to be more efficient and flexible than CDNs and hold great potential for applications in both biological studies and medicine. Here, we review the progress that has been made for all three genome editing technologies in modifying both cells and model organisms, compare important aspects of each approach, and summarize the applications of these tools in disease modeling and gene therapy. In the end, we discuss future prospects of the field. PMID:24665839

Cai, Mi; Yang, Yi

2014-02-01

316

A Potential Application of Canaloplasty in Glaucoma Gene Therapy  

PubMed Central

Canaloplasty, a recently developed nonpenetrating glaucoma surgical approach, may restore physiological outflow routes in primary open-angle glaucoma with less risk of severe postoperative complications than trabeculectomy. Since the inner wall of Schlemm's canal (SC) is directly in contact with the trabecular meshwork (TM) for 360° and the catheter device used in canaloplasty allows viscoelastic to be injected into the entire length of SC, canaloplasty might also be used to perform SC/TM-targeted delivery of transgene vectors for glaucoma gene therapy. This hypothesized new method for transgene delivery may give the transgene access to the entire inner wall of SC and the whole juxtacanalicular region of the TM and allow the transgene to be expressed in both the TM and SC without affecting the cornea, iris, and ciliary body. This strategy might have a greater trabecular outflow resistance-decreasing effect than either the genetic or surgical approach alone. PMID:23888250

Tian, Baohe; Kaufman, Paul L.

2013-01-01

317

Toward a gene therapy for neurological and somatic MPSIIIA  

PubMed Central

Mucopolysaccharidosis Type IIIA (MPSIIIA) represents an unmet medical need. MPSIIIA shares with many other lysosomal storage disorders (LSD) the characteristic of being a severe neurodegenerative disease accompanied by mild somatic involvement. Thus, the main target organ for the development of new treatments is the central nervous system (CNS), but overall clinical efficacy would be greatly enhanced by simultaneous correction of peripheral disease. We have recently developed a novel treatment for MPSIIIA based on the delivery to the cerebrospinal fluid of serotype 9 adeno-associated virus (AAV9)-derived vectors. This gene therapy strategy corrected both CNS and somatic pathology in animal models through widespread transduction of CNS, peripheral nervous system (PNS), and liver. The work set the grounds for the clinical translation of the approach to treat MPSIIIA in humans. Here we discuss some important considerations that further support the applicability of this treatment to MPSIIIA and other LSD with CNS and somatic involvement. PMID:25003015

Haurigot, Virginia; Bosch, Fatima

2013-01-01

318

Center for Gene Therapy of Cystic Fibrosis Call for Pilot Grant Applications  

E-print Network

Center for Gene Therapy of Cystic Fibrosis Call for Pilot Grant Applications http://genetherapy.genetics.uiowa.edu/ The University of Iowa Center for Gene Therapy of Cystic Fibrosis is accepting applications for pilot of cystic fibrosis and disease pathophysiology in cystic fibrosis. Pilot grants, with budgets of up to $75

319

Prospects for cationic polymers in gene and oligonucleotide therapy against cancer  

Microsoft Academic Search

Gene and antisense\\/ribozyme therapy possesses tremendous potential for the successful treatment of genetically based diseases, such as cancer. Several cancer gene therapy strategies have already been realized in vitro, as well as in vivo. A few have even reached the stage of clinical trials, most of them phase I, while some antisense strategies have advanced to phase II and III

Thomas Merdan; Thomas Kissel

2002-01-01

320

Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative Conditioning  

Microsoft Academic Search

Hematopoietic stem cell (HSC) gene therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) has shown limited clinical efficacy because of the small proportion of engrafted genetically corrected HSCs. We describe an improved protocol for gene transfer into HSCs associated with nonmyeloablative conditioning. This protocol was used in two patients for whom enzyme replacement therapy was not available, which allowed

Alessandro Aiuti; Shimon Slavin; Memet Aker; Francesca Ficara; Sara Deola; Alessandra Mortellaro; Shoshana Morecki; Grazia Andolfi; Antonella Tabucchi; Filippo Carlucci; Enrico Marinello; Federica Cattaneo; Sergio Vai; Paolo Servida; Roberto Miniero; Maria Grazia Roncarolo; Claudio Bordignon

2002-01-01

321

Progress and problems with the use of viral vectors for gene therapy  

Microsoft Academic Search

Gene therapy has a history of controversy. Encouraging results are starting to emerge from the clinic, but questions are still being asked about the safety of this new molecular medicine. With the development of a leukaemia-like syndrome in two of the small number of patients that have been cured of a disease by gene therapy, it is timely to contemplate

Clare E. Thomas; Anja Ehrhardt; Mark A. Kay

2003-01-01

322

Progress and prospects: Immunobiology of gene therapy for neurodegenerative disease: prospects and risks  

Microsoft Academic Search

Gene therapy for neurological, and in particular neurodegenerative, disease is now a reality. A number of early phase clinical trials have been completed and several are currently in progress. In view of this, it is critically important to evaluate the immunological risk associated with neurological gene therapy, which has clear implications for trial safety and efficacy. Moreover, it is imperative

M M McMenamin; M J A Wood; MJA Wood

2010-01-01

323

A large preclinical animal model to assess ex vivo skin gene therapy applications  

Microsoft Academic Search

Because of its easy accessibility, the skin is a very attractive target for gene therapy purposes. To study potential clinical applications in a preclinical setting, appropriate animal models are needed. Pig skin is very similar to human skin, and a variety of human diseases that are potentially amenable to gene therapy applications also occur in pigs. Only a few studies

Wolfgang Pfützner; Mohammed R. Joari; Ruth-Ann Foster; Jonathan C. Vogel

2006-01-01

324

Rapamycin Enhances Adenovirus-Mediated Cancer Imaging and Therapy in Pre-Immunized Murine Hosts  

PubMed Central

Tumor-specific adenoviral vectors comprise a fruitful gene-based diagnostic imaging and therapy research area for advanced stage of cancer, including metastatic disease. However, clinical translation of viral vectors has encountered considerable obstacles, largely due to host immune responses against the virus. Here, we explored the utilization of an immunosuppressant, rapamycin, to circumvent the anti-adenovirus immunity in immunocompetent murine prostate cancer models. Rapamycin diminished adenoviral-induced acute immune response by inhibiting NF-?B activation; it also reduced the scale and delayed the onset of inflammatory cytokine secretion. Further, we found that rapamycin abrogated anti-adenovirus antibody production and retarded the function of myeloid cells and lymphocytes that were activated upon viral administration in pre-immunized hosts. Thus, the co-administration of rapamycin prolonged and enhanced adenovirus-delivered transgene expression in vivo, and thereby augmented the imaging capability of adenoviral vectors in both bioluminescent and positron emission tomography modalities. Furthermore, we showed that despite an excellent response of cancer cells to a cytotoxic gene therapeutic vector in vitro, only minimal therapeutic effects were observed in vivo in pre-immunized mice. However, when we combined gene therapy with transient immunosuppression, complete tumor growth arrest was achieved. Overall, transient immunosuppression by rapamycin was able to boost the diagnostic utility and therapeutic potentials of adenoviral vectors. PMID:24023896

Jiang, Ziyue Karen; Johnson, Mai; Moughon, Diana L.; Kuo, Jennifer; Sato, Makoto; Wu, Lily

2013-01-01

325

Immunotargeted nanoshells for integrated cancer imaging and therapy.  

PubMed

Nanoshells are a novel class of optically tunable nanoparticles that consist of a dielectric core surrounded by a thin gold shell. Based on the relative dimensions of the shell thickness and core radius, nanoshells may be designed to scatter and/or absorb light over a broad spectral range including the near-infrared (NIR), a wavelength region that provides maximal penetration of light through tissue. The ability to control both wavelength-dependent scattering and absorption of nanoshells offers the opportunity to design nanoshells which provide, in a single nanoparticle, both diagnostic and therapeutic capabilities. Here, we demonstrate a novel nanoshell-based all-optical platform technology for integrating cancer imaging and therapy applications. Immunotargeted nanoshells are engineered to both scatter light in the NIR enabling optical molecular cancer imaging and to absorb light, allowing selective destruction of targeted carcinoma cells through photothermal therapy. In a proof of principle experiment, dual imaging/therapy immunotargeted nanoshells are used to detect and destroy breast carcinoma cells that overexpress HER2, a clinically relevant cancer biomarker. PMID:15826113

Loo, Christopher; Lowery, Amanda; Halas, Naomi; West, Jennifer; Drezek, Rebekah

2005-04-01

326

Gastric inhibitory polypeptide receptor (GIPR) is a promising target for imaging and therapy in neuroendocrine tumors  

PubMed Central

Background Ligands binding the somatostatin receptor type 2 (SSTR2) are useful for imaging and treatment of neuroendocrine tumors (NETs), but not all tumors express high levels of these receptors. The aim of this study was to evaluate gene expression of new therapeutic targets in NETs relative to SSTR2. Methods RNA was extracted from 103 primary small bowel (SBNET) and pancreatic neuroendocrine tumors (PNET), matched normal tissue, and 123 metastases. Expression of 12 candidate genes was measured by quantitative PCR normalized to internal controls; candidate gene expression was compared to SSTR2. Results Relative to normal tissue, primary NET expression of SSTR2, GPR98, BRS3, GIPR, GRM1, and OPRK1 were increased by 3, 8, 13, 13, 17, and 20-fold, respectively. Similar changes were found in metastases. While most candidate genes showed lower absolute expression than SSTR2, absolute GIPR expression was closest to SSTR2 (mean dCT 3.6 vs. 2.7, p=0.01). Absolute OPRK1 and OXTR expression varied significantly by primary tumor type and was close to SSTR2 in SBNETs but not PNETs. Conclusions Compared to the current treatment standard SSTR2, GIPR has only somewhat lower absolute gene expression in tumor tissue but much lower expression in normal tissue, making it a promising new target for NET imaging and therapy. PMID:24238043

Sherman, Scott K.; Carr, Jennifer C.; Wang, Donghong; O’Dorisio, M. Sue; O’Dorisio, Thomas M.; Howe, James R.

2013-01-01

327

Theranostic applications of nanomaterials in cancer: Drug delivery, image-guided therapy and multifunctional platforms  

PubMed Central

Successful cancer management depends on accurate diagnostics along with specific treatment protocols. Current diagnostic techniques need to be improved to provide earlier detection capabilities, and traditional chemotherapy approaches to cancer treatment are limited by lack of specificity and systemic toxicity. This review highlights advances in nanotechnology that have allowed the development of multifunctional platforms for cancer detection, therapy, and monitoring. Nanomaterials can be used as MRI, optical imaging, and photoacoustic imaging contrast agents. When used as drug carriers, nanoformulations can increase tumor exposure to therapeutic agents and result in improved treatment effects by prolonging circulation times, protecting entrapped drugs from degradation, and enhancing tumor uptake through the EPR effect as well as receptor-mediated endocytosis. Multiple therapeutic agents such as chemotherapy, antiangiogenic, or gene therapy agents can be simultaneously delivered by nanocarriers to tumor sites to enhance the effectiveness of therapy. Additionally, imaging and therapy agents can be co-delivered to provide seamless integration of diagnostics, therapy and follow-up, and different therapeutic modalities such as chemotherapy and hyperthermia can be coadministered to take advantage of synergistic effects. Liposomes, metallic nanoparticles, polymeric nanoparticles, dendrimers, carbon nanotubes, and quantum dots are examples of nanoformulations that can be used as multifunctional platforms for cancer theranostics. Nanomedicine approaches in cancer have great potential for clinically translatable advances that can positively impact the overall diagnostic and therapeutic process, and result in enhanced quality of life for cancer patients. However, a concerted scientific effort is still necessary to fully explore long-term risks, effects, and precautions for safe human use. PMID:21947761

Fernandez-Fernandez, Alicia; Manchanda, Romila

2011-01-01

328

www.elsevier.com/locate/ejcts Acceptance of gene therapy by the heart surgery patient  

E-print Network

Objective: The aim of the present study was to evaluate the attitude of cardiac surgery patients towards gene therapeutic approaches to heart disease. Methods: One hundred and fifty patients having undergone coronary artery bypass grafting ðn 97Þ, valvular operations ðn 40Þ or combined procedures ðn 13Þ were personally interviewed prior to discharge using a self designed questionnaire. Results: Seventeen percent of the surveyed patients were unable to complete the interview because of total non-understanding of the topic. Of the remaining patients, 33 % could basically define the term ‘gene’. After explanation of gene therapy principles 70 % believed that gene therapy protocols had already been started clinically. Fifty-two percent would accept enrollment in a clinical trial (85 % in cases of otherwise incurable disease). If clinical gene transfer would be carried out 73 % of patients would accept adenovirus as a vector, 94 and 80%, respectively, would accept catheter-based intervention or surgery for performance of gene therapy. Fifty-four percent would agree to a prophylactic gene therapy protocol. Conclusions: We conclude that the general attitude of heart surgery patients regarding gene therapy is positive. A considerable number of patients are unable to understand the basic principles of gene therapy. These data can be useful for planning of clinical gene

Johannes Bonatti; Christa Haeusler; Er Klaus; Monika Fink; Angelika Hammerer-lercher; Günther Laufer

329

Current Status and Prospects of Gene Therapy for the Inner Ear  

PubMed Central

Abstract Inner ear diseases are common and often result in hearing disability. Sensorineural hearing loss is the main cause of hearing disability. So far, no effective treatment is available although some patients may benefit from a hearing aid equipped with a hearing amplifier or from cochlear implantation. Inner ear gene therapy has become an emerging field of study for the treatment of hearing disability. Numerous new discoveries and tremendous advances have been made in inner ear gene therapy including gene vectors, routes of administration, and therapeutic genes and targets. Gene therapy may become a treatment option for inner ear diseases in the near future. In this review, we summarize the current state of inner ear gene therapy including gene vectors, delivery routes, and therapeutic genes and targets by examining and analyzing publications on inner ear gene therapy from the literature and patent documents, and identify promising patents, novel techniques, and vital research projects. We also discuss the progress and prospects of inner ear gene therapy, the advances and shortcomings, with possible solutions in this field of research. PMID:21338273

Huang, Aji

2011-01-01

330

Feasibility of a predictive model of Hsp70b-activated gene therapy protein expression during ultrasound hyperthermia  

E-print Network

Gene therapy has been heralded as a possible approach to a variety of diseases and conditions, ranging from cancer and heart disease to blindness and neurodegenerative diseases. However, progress in gene therapy requires ...

Silcox, Christina Elise

2014-01-01

331

GINI: From ISH Images to Gene Interaction Networks  

PubMed Central

Accurate inference of molecular and functional interactions among genes, especially in multicellular organisms such as Drosophila, often requires statistical analysis of correlations not only between the magnitudes of gene expressions, but also between their temporal-spatial patterns. The ISH (in-situ-hybridization)-based gene expression micro-imaging technology offers an effective approach to perform large-scale spatial-temporal profiling of whole-body mRNA abundance. However, analytical tools for discovering gene interactions from such data remain an open challenge due to various reasons, including difficulties in extracting canonical representations of gene activities from images, and in inference of statistically meaningful networks from such representations. In this paper, we present GINI, a machine learning system for inferring gene interaction networks from Drosophila embryonic ISH images. GINI builds on a computer-vision-inspired vector-space representation of the spatial pattern of gene expression in ISH images, enabled by our recently developed system; and a new multi-instance-kernel algorithm that learns a sparse Markov network model, in which, every gene (i.e., node) in the network is represented by a vector-valued spatial pattern rather than a scalar-valued gene intensity as in conventional approaches such as a Gaussian graphical model. By capturing the notion of spatial similarity of gene expression, and at the same time properly taking into account the presence of multiple images per gene via multi-instance kernels, GINI is well-positioned to infer statistically sound, and biologically meaningful gene interaction networks from image data. Using both synthetic data and a small manually curated data set, we demonstrate the effectiveness of our approach in network building. Furthermore, we report results on a large publicly available collection of Drosophila embryonic ISH images from the Berkeley Drosophila Genome Project, where GINI makes novel and interesting predictions of gene interactions. Software for GINI is available at http://sailing.cs.cmu.edu/Drosophila_ISH_images/ PMID:24130465

Puniyani, Kriti; Xing, Eric P.

2013-01-01

332

Cytokine pattern in cystic fibrosis patients during antibiotic therapy and gene therapy using adenoviral vector.  

PubMed

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite improvements in treatment, pulmonary disease still remains the primary cause of death among these patients. In order to introduce a normal CFTR gene copy into airway epithelial cells, adenoviral vectors (AV) have been developed. AV are known to induce an inflammatory reaction that limits transgene expression, and can be potentially harmful. No human study has clearly monitored simultaneously, systemic and local inflammatory reaction, during AV administration. We report here the levels of C-reactive protein (CRP), interleukin (IL)-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 receptor antagonist (IL-1Ra) in plasma and bronchoalveolar lavage fluid (BALF) from six cystic fibrosis patients receiving AV encoding CFTR (AdCFTR). AdCFTR was administered to three cohorts of two patients into the nose on day 0, at doses ranging from 105 to 4 x 108 plaque-forming units (pfu), followed, on day 1, by aerosolization of 107 to 5.4 x 108 pfu. In order to ensure that patients were in the best clinical condition, and to further attenuate the broncho-pulmonary inflammation secondary to bacterial infection, they received antibiotic therapy, two weeks prior to AdCFTR administration, until 9 to 11 days after. We found that antibiotics markedly decreased CRP, TNF-alpha, IL-6, IL-1Ra levels in blood. In BALF, antibiotics slightly decreased TNF-alpha levels but had no effect on IL-8 and IL-1Ra, while IL-6 levels increased. AdCFTR administration did not induce any systemic or local cytokine release. In both blood and BALF, CRP, IL-8, IL-1Ra, TNF-alpha decreased, while IL-6 levels increased between day -7 and day 3. One patient presented an asymptomatic increase of all parameters in the BALF on day 7. Twenty one days later, he displayed a clinical deterioration suggestive of an exacerbation. In conclusion, this study demonstrates that antibiotic administration tends to attenuate systemic but not local broncho-pulmonary inflammation in CF patients. In the setting of our study, AdCFTR administration did not induce cytokine release. Further studies are necessary to investigate other inflammatory markers and the mechanisms involved during AV-mediated gene transfer for a better understanding of the immune reaction, which continues to hamper the development of gene therapy for CF patients. PMID:12231476

Reix, Philippe; Bellon, Gabriel; Bienvenu, Jacques; Pavirani, Andrea; Levrey-Hadden, Hélène

2002-01-01

333

78 FR 26794 - Prospective Grant of Start-Up Exclusive Evaluation Option License Agreement: Gene Therapy and...  

Federal Register 2010, 2011, 2012, 2013

...Option License Agreement: Gene Therapy and Cell-Based Therapy for Cardiac Arrhythmias...may be limited to ``Gene therapy and cell-based therapy for cardiac arrhythmias...activated adenylyl cyclase, as well as cardiac cells or cardiac-like cells derived from...

2013-05-08

334

Gene Therapy (2000) 7, 445449 2000 Macmillan Publishers Ltd All rights reserved 0969-7128/00 $15.00  

E-print Network

Gene Therapy (2000) 7, 445­449 © 2000 Macmillan Publishers Ltd All rights reserved 0969-7128/00 $15 hemiparkinsonism by gene therapy using genetically modified myoblasts L Cao1,2 , Y-C Zhao3 , Z-H Jiang4 , D-H Xu1 by RT-PCR and immunohisto- Keywords: Parkinson's disease; gene therapy; myoblasts; tyrosine hydroxylase

Tian, Weidong

335

H U M A N GENE THERAPY 2:115-122 (1991) Mary Ann Liebert, Inc., Publishers  

E-print Network

H U M A N GENE THERAPY 2:115-122 (1991) Mary Ann Liebert, Inc., Publishers H u m a n G e n e T h e engineering but an acceptance of somatic-cell gene therapy as treatment for disease. Internationally, numerous legitimacy ofsomatic-cell gene therapy for the cure ofdisease. T he debate over the ethical issues related

336

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked  

E-print Network

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already markers and preserva- tion of outer plexiform layer thickness. Efficacy of gene therapy in these large

Bushman, Frederic

337

Gene Therapy (2002) 9, 713718 2002 Nature Publishing Group All rights reserved 0969-7128/02 $25.00  

E-print Network

Gene Therapy (2002) 9, 713­718 2002 Nature Publishing Group All rights reserved 0969-7128/02 $25.00 www.nature.com/gt Chromosome engineering: prospects for gene therapy BR Grimes1 , PE Warburton2 and CJ and the potential for downstream applications in gene therapy were presented at the Artificial Chromosome Session

Warburton, Peter E.

338

[CANCER RESEARCH 64, 53905397, August 1, 2004] Effective Gene-Viral Therapy for Telomerase-Positive Cancers by Selective  

E-print Network

[CANCER RESEARCH 64, 5390­5397, August 1, 2004] Effective Gene-Viral Therapy for Telomerase Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical Gene-viral therapy, which uses replication-selective transgene-express- ing viruses to manage tumors

Tian, Weidong

339

Analysis Of S/MAR Vectors For Gene Therapy A Thesis Submitted For The Degree Of Doctor Of Philosophy  

E-print Network

1 Analysis Of S/MAR Vectors For Gene Therapy In Muscle A Thesis Submitted For The Degree Of Doctor caused by this condition are being investigated, one of which is gene therapy. This approach is used of this vector for use as a gene therapy vector in muscle cells in order to treat MD. In this study, the long

Sheldon, Nathan D.

340

[CANCER RESEARCH 62, 42734281, August 1, 2002] Adenoviral Gene Therapy for Renal Cancer Requires Retargeting to Alternative  

E-print Network

[CANCER RESEARCH 62, 4273­4281, August 1, 2002] Adenoviral Gene Therapy for Renal Cancer Requires and David T. Curiel2 Division of Human Gene Therapy, Departments of Medicine, Pathology, and Surgery, and Gene Therapy Center [Y. S. H., J. L. B., A. K., P. N., V. K., I. D., M. W., X. L., A. H., D. T. C

Hemminki, Akseli

341

N3-substituted thymidine bioconjugates for cancer therapy and imaging  

PubMed Central

The compound class of 3-carboranyl thymidine analogues (3CTAs) are boron delivery agents for boron neutron capture therapy (BNCT), a binary treatment modality for cancer. Presumably, these compounds accumulate selectively in tumor cells via intracellular trapping, which is mediated by hTK1. Favorable in vivo biodistribution profiles of 3CTAs led to promising results in preclinical BNCT of rats with intracerebral brain tumors. This review presents an overview on the design, synthesis, and biological evaluation of first- and second-generation 3CTAs. Boronated nucleosides developed prior to 3CTAs for BNCT and non-boronated N3-substituted thymidine conjugates for other areas of cancer therapy and imaging are also described. In addition, basic features of carborane clusters, which are used as boron moieties in the design and synthesis of 3CTAs, and the biological and structural features of TK1-like enzymes, which are the molecular targets of 3CTAs, are discussed. PMID:23617430

Khalil, Ahmed; Ishita, Keisuke; Ali, Tehane; Tjarks, Werner

2013-01-01

342

Preface Current Gene Therapy, 2013, Vol. 13, No. 1 1 It is not superstition that worries me, Herr Doctor, but genes and chromosomes  

E-print Network

Preface Current Gene Therapy, 2013, Vol. 13, No. 1 1 Preface « It is not superstition that worries me, Herr Doctor, but genes and chromosomes » Inspector Kemp, from the movie Young Frankenstein, 1974. Current Gene Therapy is focused on genes; how to manipulate coding sequences, transferring them

Boyer, Edmond

343

HUMAN GENE THERAPY 19:12491260 (November 2008) Mary Ann Liebert, Inc.  

E-print Network

HUMAN GENE THERAPY 19:1249­1260 (November 2008) © Mary Ann Liebert, Inc. DOI: 10.1089/hum.2008.059 Physiological Effects of High- and Low-Voltage Pulse Combinations for Gene Electrotransfer in Muscle Pernille and Lluis M. Mir3 Abstract Gene transfer by electroporation is gaining momentum now that high-level, long

Paris-Sud XI, Université de

344

930. Engineering Human Deoxycytidine Kinase for Improved Prodrug Sensitivity for Cancer Gene Therapy  

Microsoft Academic Search

Suicide gene therapy, unlike chemotherapy, offers a localized and selective cancer treatment. This is accomplished through the introduction of a gene encoding an enzyme into cancer cells. Upon administration of the prodrug, the enzyme converts the prodrug selectively into its toxic form, thereby resulting in the elimination of cancer cells. However, there are several limitations of the current gene delivery

Candice L. Willmon; Margaret E. Black

2006-01-01

345

In Vivo Gene Therapy of Hemophilia B: Sustained Partial Correction in Factor IX-Deficient Dogs  

Microsoft Academic Search

The liver represents a model organ for gene therapy. A method has been developed for hepatic gene transfer in vivo by the direct infusion of recombinant retroviral vectors into the portal vasculature, which results in the persistent expression of exogenous genes. To determine if these technologies are applicable for the treatment of hemophilia B patients, preclinical efficacy studies were done

Mark A. Kay; Steven Rothenberg; Charles N. Landen; Dwight A. Bellinger; Frances Leland; Carol Toman; Milton Finegold; Arthur R. Thompson; M. S. Read; Kenneth M. Brinkhous; Savio L. C. Woo

1993-01-01

346

Alkylphosphocholine Analogs for Broad-Spectrum Cancer Imaging and Therapy  

PubMed Central

Many solid tumors contain an overabundance of phospholipid ethers relative to normal cells. Capitalizing on this difference, we created cancer-targeted alkylphosphocholine (APC) analogs through structure-activity analyses. Depending on the iodine isotope used, radioiodinated APC analog CLR1404 was used as either a positron emission tomography (PET) imaging (124I) or molecular radiotherapeutic (131I) agent. CLR1404 analogs displayed prolonged tumor-selective retention in 55 in vivo rodent and human cancer and cancer stem cell models. 131I-CLR1404 also displayed efficacy (tumor growth suppression and survival extension) in a wide range of human tumor xenograft models. Human PET/CT (computed tomography) and SPECT (single-photon emission computed tomography)/CT imaging in advanced-cancer patients with 124I-CLR1404 or 131I-CLR1404, respectively, demonstrated selective uptake and prolonged retention in both primary and metastatic malignant tumors. Combined application of these chemically identical APC-based radioisosteres will enable personalized dual modality cancer therapy of using molecular 124I-CLR1404 tumor imaging for planning 131I-CLR1404 therapy. PMID:24920661

Weichert, Jamey P.; Clark, Paul A.; Kandela, Irawati K.; Vaccaro, Abram M.; Clarke, William; Longino, Marc A.; Pinchuk, Anatoly N.; Farhoud, Mohammed; Swanson, Kyle I.; Floberg, John M.; Grudzinski, Joseph; Titz, Benjamin; Traynor, Anne M.; Chen, Hong-En; Hall, Lance T.; Pazoles, Christopher J.; Pickhardt, Perry J.; Kuo, John S.

2015-01-01

347

Parameters Affecting Image-guided, Hydrodynamic Gene Delivery to Swine Liver  

PubMed Central

Development of a safe and effective method for gene delivery to hepatocytes is a critical step toward gene therapy for liver diseases. Here, we assessed the parameters for gene delivery to the livers of large animals (pigs, 40–65?kg) using an image-guided hydrodynamics-based procedure that involves image-guided catheter insertion into the lobular hepatic vein and hydrodynamic injection of reporter plasmids using a computer-controlled injector. We demonstrated that injection parameters (relative position of the catheter in the hepatic vasculature, intravascular pressure upon injection, and injection volume) are directly related to the safety and efficiency of the procedure. By optimizing these parameters, we explored for the first time, the advantage of the procedure for sequential injections to multiple lobes in human-sized pigs. The optimized procedure resulted in sustained expression of the human ?-1 antitrypsin gene in livers for more than 2 months after gene delivery. In addition, repeated hydrodynamic gene delivery was safely conducted and no adverse events were seen in the entire period of the study. Our results support the clinical applicability of the image-guided hydrodynamic gene delivery method for the treatment of liver diseases. PMID:24129227

Kamimura, Kenya; Suda, Takeshi; Zhang, Guisheng; Aoyagi, Yutaka; Liu, Dexi

2013-01-01

348

Prospective on the potential of imaging gene expression  

SciTech Connect

The feasibility of the non-invasive imaging of gene expression is explored. Calculations of the possibility of the direct imaging of specific messenger RNA with radiolabeled antisense are discussed. In addition, possible mechanism for the amplification of the biological signal to enhance image detection are discussed.

Taylor, Scott E; Budinger, Thomas F.

2000-06-01

349

Advancing Translational Research Through the NHLBI Gene Therapy Resource Program (GTRP)  

PubMed Central

Abstract Translational research is a lengthy, complex, and necessary endeavor in order to bring basic science discoveries to clinical fruition. The NIH offers several programs to support translational research including an important resource established specifically for gene therapy researchers—the National Heart, Lung, and Blood Institute (NHLBI) Gene Therapy Resource Program (GTRP). This paper reviews the core components of the GTRP and describes how the GTRP provides researchers with resources that are critical to advancing investigational gene therapy products into clinical testing. PMID:23692378

Benson, Janet; Cornetta, Kenneth; Diggins, Margaret; Johnston, Julie C.; Sepelak, Susan; Wang, Gensheng; Wilson, James M.; Wright, J. Fraser; Skarlatos, Sonia I.

2013-01-01

350

Advancing translational research through the NHLBI Gene Therapy Resource Program (GTRP).  

PubMed

Abstract Translational research is a lengthy, complex, and necessary endeavor in order to bring basic science discoveries to clinical fruition. The NIH offers several programs to support translational research including an important resource established specifically for gene therapy researchers-the National Heart, Lung, and Blood Institute (NHLBI) Gene Therapy Resource Program (GTRP). This paper reviews the core components of the GTRP and describes how the GTRP provides researchers with resources that are critical to advancing investigational gene therapy products into clinical testing. PMID:23692378

McDonald, Cheryl L; Benson, Janet; Cornetta, Kenneth; Diggins, Margaret; Johnston, Julie C; Sepelak, Susan; Wang, Gensheng; Wilson, James M; Wright, J Fraser; Skarlatos, Sonia I

2013-03-01

351

Cancer gene therapy using a survivin mutant adenovirus  

PubMed Central

We have constructed a replication-deficient adenovirus encoding a nonphosphorylatable Thr34?Ala mutant of the apoptosis inhibitor survivin (pAd-T34A) to target tumor cell viability in vitro and in vivo. Infection with pAd-T34A caused spontaneous apoptosis in cell lines of breast, cervical, prostate, lung, and colorectal cancer. In contrast, pAd-T34A did not affect cell viability of proliferating normal human cells, including fibroblasts, endothelium, or smooth muscle cells. Infection of tumor cells with pAd-T34A resulted in cytochrome c release from mitochondria, cleavage of approximately 46-kDa upstream caspase-9, processing of caspase-3 to the active subunits of approximately 17 and 19 kDa, and increased caspase-3 catalytic activity. When compared with chemotherapeutic regimens, pAd-T34A was as effective as taxol and considerably more effective than adriamycin in induction of tumor cell apoptosis and enhanced taxol-induced cell death. In three xenograft breast cancer models in immunodeficient mice, pAd-T34A suppressed de novo tumor formation, inhibited by approximately 40% the growth of established tumors, and reduced intraperitoneal tumor dissemination. Tumors injected with pAd-T34A exhibited loss of proliferating cells and massive apoptosis by in situ internucleosomal DNA fragmentation. These data suggest that adenoviral targeting of the survivin pathway may provide a novel approach for selective cancer gene therapy. PMID:11581299

Mesri, Mehdi; Wall, Nathan R.; Li, Jia; Kim, Richard W.; Altieri, Dario C.

2001-01-01

352

Melanoma differentiation associated gene-7 (mda-7): a novel anti-tumor gene for cancer gene therapy.  

PubMed Central

BACKGROUND: The mda-7 gene (melanoma differentiation associated gene-7) is a novel tumor suppressor gene. The anti-proliferative activity of MDA-7 has been previously reported. In this report, we analyze the anti-tumor efficacy of Ad-mda7 in a broad spectrum of cancer lines. MATERIALS AND METHODS: Ad-mda7-transduced cancer or normal cell lines were assayed for cell proliferation (tritiated thymidine incorporation assay, Alamar blue assay, and trypan-blue exclusion assay), apoptosis (TUNEL, and Annexin V staining visualized by fluorescent microscopy or FACs analysis), and cell cycle regulation (Propidium Iodide staining and FACs analysis). RESULTS: Ad-mda7 treatment of tumor cells resulted in growth inhibition and apoptosis in a temporal and dose-dependent manner. The anti-tumor effects were independent of the genomic status of p53, RB, p16, ras, bax, and caspase 3 in these cells. In addition, normal cell lines did not show inhibition of proliferation or apoptotic response to Ad-mda7. Moreover, Ad-mda7-transduced cancer cells secreted a soluble form of MDA-7 protein. Thus, Ad-mda7 may represent a novel gene-therapeutic agent for the treatment of a variety of cancers. CONCLUSIONS: The potent and selective killing activity of Ad-mda7 in cancer cells but not in normal cells makes this vector a potential candidate for cancer gene therapy. PMID:11471572

Mhashilkar, A. M.; Schrock, R. D.; Hindi, M.; Liao, J.; Sieger, K.; Kourouma, F.; Zou-Yang, X. H.; Onishi, E.; Takh, O.; Vedvick, T. S.; Fanger, G.; Stewart, L.; Watson, G. J.; Snary, D.; Fisher, P. B.; Saeki, T.; Roth, J. A.; Ramesh, R.; Chada, S.

2001-01-01

353

Internal ribosome entry site-based vectors for combined gene therapy  

PubMed Central

Gene therapy appears as a promising strategy to treat incurable diseases. In particular, combined gene therapy has shown improved therapeutic efficiency. Internal ribosome entry sites (IRESs), RNA elements naturally present in the 5’ untranslated regions of a few mRNAs, constitute a powerful tool to co-express several genes of interest. IRESs are translational enhancers allowing the translational machinery to start protein synthesis by internal initiation. This feature allowed the design of multi-cistronic vectors expressing several genes from a single mRNA. IRESs exhibit tissue specificity, and drive translation in stress conditions when the global cell translation is blocked, which renders them useful for gene transfer in hypoxic conditions occurring in ischemic diseases and cancer. IRES-based viral and non viral vectors have been used successfully in preclinical and clinical assays of combined gene therapy and resulted in therapeutic benefits for various pathologies including cancers, cardiovascular diseases and degenerative diseases.

Renaud-Gabardos, Edith; Hantelys, Fransky; Morfoisse, Florent; Chaufour, Xavier; Garmy-Susini, Barbara; Prats, Anne-Catherine

2015-01-01

354

A novel fusion suicide gene yeast CDglyTK plays a role in radio-gene therapy of nasopharyngeal carcinoma  

Microsoft Academic Search

To investigate a novel suicide gene for nasopharyngeal carcinoma (NPC) therapy, the yCDglyTK gene was constructed by fusing yeast cytosine deaminase (CD) and herpes simplex type 1 thymidine kinase. The expression of the yCDglyTK gene was detected by RT-PCR and Western blotting, and its bioactivity was demonstrated by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. An animal study was carried out

Kun Xia; Desheng Liang; Aifa Tang; Yong Feng; Junyi Zhang; Qian Pan; Zhigao Long; Heping Dai; Fang Cai; Lingqian Wu; Suping Zhao; Zhuchu Chen; Jiahui Xia

2004-01-01

355

Gold Nanoconstructs for Multimodal Diagnostic Imaging and Photothermal Cancer Therapy  

NASA Astrophysics Data System (ADS)

Cancer accounts for nearly 1 out of every 4 deaths in the United States, and because conventional treatments are limited by morbidity and off-target toxicities, improvements in cancer management are needed. This thesis further develops nanoparticle-assisted photothermal therapy (NAPT) as a viable treatment option for cancer patients. NAPT enables localized ablation of disease because heat generation only occurs where tissue permissive near-infrared (NIR) light and absorbing nanoparticles are combined, leaving surrounding normal tissue unharmed. Two principle approaches were investigated to improve the specificity of this technique: multimodal imaging and molecular targeting. Multimodal imaging affords the ability to guide NIR laser application for site-specific NAPT and more holistic characterization of disease by combining the advantages of several diagnostic technologies. Towards the goal of image-guided NAPT, gadolinium-conjugated gold-silica nanoshells were engineered and demonstrated to enhance imaging contrast across a range of diagnostic modes, including T1-weighted magnetic resonance imaging, X-Ray, optical coherence tomography, reflective confocal microscopy, and two-photon luminescence in vitro as well as within an animal tumor model. Additionally, the nanoparticle conjugates were shown to effectively convert NIR light to heat for applications in photothermal therapy. Therefore, the broad utility of gadolinium-nanoshells for anatomic localization of tissue lesions, molecular characterization of malignancy, and mediators of ablation was established. Molecular targeting strategies may also improve NAPT by promoting nanoparticle uptake and retention within tumors and enhancing specificity when malignant and normal tissue interdigitate. Here, ephrinA1 protein ligands were conjugated to nanoshell surfaces for particle homing to overexpressed EphA2 receptors on prostate cancer cells. In vitro, successful targeting and subsequent photothermal ablation of prostate cancer cells was achieved with negligible nanoshell binding to normal cells. In vivo however, ephrinA1-nanoshells did not promote enhanced therapeutic outcomes in mice bearing subcutaneous prostate cancer tumors treated with NAPT compared to nontargeted particles. Nonetheless, both treatment groups demonstrated effective ablation of prostate tumors, as evidenced by tumor tissue regression. Further investigation is warranted to overcome probable protein immunogenicity that offsets ephrinA1 targeting in vivo. With future study, photothermal therapy with multimodal gadolinium-conjugated and molecularly targeted nanoshells may offer a viable treatment option for cancer patients in the clinic.

Coughlin, Andrew James

356

A promising gene delivery system developed from PEGylated MoS2 nanosheets for gene therapy  

PubMed Central

A new class of two-dimensional (2D) nanomaterial, transition metal dichalcogenides (TMDCs) such as MoS2, MoSe2, WS2, and WSe2 which have fantastic physical and chemical properties, has drawn tremendous attention in different fields recently. Herein, we for the first time take advantage of the great potential of MoS2 with well-engineered surface as a novel type of 2D nanocarriers for gene delivery and therapy of cancer. In our system, positively charged MoS2-PEG-PEI is synthesized with lipoic acid-modified polyethylene glycol (LA-PEG) and branched polyethylenimine (PEI). The amino end of positively charged nanomaterials can bind to the negatively charged small interfering RNA (siRNA). After detection of physical and chemical characteristics of the nanomaterial, cell toxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Polo-like kinase 1 (PLK1) was investigated as a well-known oncogene, which was a critical regulator of cell cycle transmission at multiple levels. Through knockdown of PLK1 with siRNA carried by novel nanovector, qPCR and Western blot were used to measure the interfering efficiency; apoptosis assay was used to detect the transfection effect of PLK1. All results showed that the novel nanocarrier revealed good biocompatibility, reduced cytotoxicity, as well as high gene-carrying ability without serum interference, thus would have great potential for gene delivery and therapy. PMID:25386104

2014-01-01

357

News Note: Gene Therapy Method Slows Tumor Growth in Mice  

Cancer.gov

NCI researchers have developed a novel method in mice of delivering genes to cancer cells, that when expressed, promote cell death. These genes, known as suicide genes, cause a cell to kill itself through a process known as apoptosis. The new technique uses the survivin gene promoter to express the suicide gene and induce apoptosis in cancer cells. This method of gene delivery effectively targeted tumor cells with a minimum effect on normal cells.

358

An integrin-targeted non-viral vector for pulmonary gene therapy  

Microsoft Academic Search

Gene therapy offers potential for the treatment of severe respiratory diseases. However, the vectors which are currently available have drawbacks limiting their therapeutic application. Here we report on an integrin-targeted, non-viral gene delivery system for pulmonary gene transfer. We demonstrate that this vector can deliver the lacZ reporter gene to the lung, transfecting bronchial epithelium and parenchymal cells with similar

R G Jenkins; S E Herrick; Q-H Meng; C Kinnon; G J Laurent; R J McAnulty; S L Hart

2000-01-01

359

Autoradiography Imaging in Targeted Alpha Therapy with Timepix Detector  

PubMed Central

There is a lack of data related to activity uptake and particle track distribution in targeted alpha therapy. These data are required to estimate the absorbed dose on a cellular level as alpha particles have a limited range and traverse only a few cells. Tracking of individual alpha particles is possible using the Timepix semiconductor radiation detector. We investigated the feasibility of imaging alpha particle emissions in tumour sections from mice treated with Thorium-227 (using APOMAB), with and without prior chemotherapy and Timepix detector. Additionally, the sensitivity of the Timepix detector to monitor variations in tumour uptake based on the necrotic tissue volume was also studied. Compartmental analysis model was used, based on the obtained imaging data, to assess the Th-227 uptake. Results show that alpha particle, photon, electron, and muon tracks were detected and resolved by Timepix detector. The current study demonstrated that individual alpha particle emissions, resulting from targeted alpha therapy, can be visualised and quantified using Timepix detector. Furthermore, the variations in the uptake based on the tumour necrotic volume have been observed with four times higher uptake for tumours pretreated with chemotherapy than for those without chemotherapy.

AL Darwish, Ruqaya; Staudacher, Alexander Hugo; Bezak, Eva; Brown, Michael Paul

2015-01-01

360

Noise evaluation of Compton camera imaging for proton therapy.  

PubMed

Compton Cameras emerged as an alternative for real-time dose monitoring techniques for Particle Therapy (PT), based on the detection of prompt-gammas. As a consequence of the Compton scattering process, the gamma origin point can be restricted onto the surface of a cone (Compton cone). Through image reconstruction techniques, the distribution of the gamma emitters can be estimated, using cone-surfaces backprojections of the Compton cones through the image space, along with more sophisticated statistical methods to improve the image quality. To calculate the Compton cone required for image reconstruction, either two interactions, the last being photoelectric absorption, or three scatter interactions are needed. Because of the high energy of the photons in PT the first option might not be adequate, as the photon is not absorbed in general. However, the second option is less efficient. That is the reason to resort to spectral reconstructions, where the incoming ? energy is considered as a variable in the reconstruction inverse problem. Jointly with prompt gamma, secondary neutrons and scattered photons, not strongly correlated with the dose map, can also reach the imaging detector and produce false events. These events deteriorate the image quality. Also, high intensity beams can produce particle accumulation in the camera, which lead to an increase of random coincidences, meaning events which gather measurements from different incoming particles. The noise scenario is expected to be different if double or triple events are used, and consequently, the reconstructed images can be affected differently by spurious data. The aim of the present work is to study the effect of false events in the reconstructed image, evaluating their impact in the determination of the beam particle ranges. A simulation study that includes misidentified events (neutrons and random coincidences) in the final image of a Compton Telescope for PT monitoring is presented. The complete chain of detection, from the beam particle entering a phantom to the event classification, is simulated using FLUKA. The range determination is later estimated from the reconstructed image obtained from a two and three-event algorithm based on Maximum Likelihood Expectation Maximization. The neutron background and random coincidences due to a therapeutic-like time structure are analyzed for mono-energetic proton beams. The time structure of the beam is included in the simulations, which will affect the rate of particles entering the detector. PMID:25658644

Ortega, P G; Torres-Espallardo, I; Cerutti, F; Ferrari, A; Gillam, J E; Lacasta, C; Llosá, G; Oliver, J F; Sala, P R; Solevi, P; Rafecas, M

2015-02-21

361

Autophagy and gene therapy combine in the treatment of liver disease.  

PubMed

Molecular biology holds the promise not only of increasing our understanding of basic cell biology, but also of advancing our ability to design targeted therapeutic methods for treating a range of diseases. One example that seems to hold tremendous potential is gene therapy, the use of exogenous DNA to replace or suppress a mutant gene in the patient's genome, or to boost the activity of a normal gene. A recent report (highlighted in a punctum in this issue of the journal) has brought autophagy into the gene therapy realm. PMID:23590992

Thompson, Debra A; Klionsky, Daniel J

2013-07-01

362

Autophagy and gene therapy combine in the treatment of liver disease  

PubMed Central

Molecular biology holds the promise not only of increasing our understanding of basic cell biology, but also of advancing our ability to design targeted therapeutic methods for treating a range of diseases. One example that seems to hold tremendous potential is gene therapy, the use of exogenous DNA to replace or suppress a mutant gene in the patient’s genome, or to boost the activity of a normal gene. A recent report (highlighted in a punctum in this issue of the journal) has brought autophagy into the gene therapy realm. PMID:23590992

Thompson, Debra A.; Klionsky, Daniel J.

2013-01-01

363

HUMAN GENE THERAPY 19:13171323 (November 2008) Mary Ann Liebert, Inc.  

E-print Network

of intravenous injection of vector, and may be important for reducing lysosomal storage in neurons (Traas et al gene therapy for chronic granulomatous disease had clonal expansion of cells with insertions near

Ponder, Katherine P.

364

Non-replicating expression vectors: applications in vaccine development and gene therapy  

PubMed Central

This review presents experimental, preclinical and clinical data illustrating the multiple uses of recombinant non-replicating virus vectors in the fields of immunoprophylaxis and gene therapy. PMID:8666067

Limbach, K. J.; Paoletti, E.

1996-01-01

365

Gene Therapy for Pediatric Cancer: State of the Art and Future Perspectives  

Microsoft Academic Search

While modern treatments have led to a dramatic improvement in survival for pediatric malignancy, toxicities are high and a significant proportion of patients remain resistant. Gene transfer offers the prospect of highly specific therapies for childhood cancer. \\

Ettore Biagi; Catherine Bollard; Raphael Rousseau; Malcolm Brenner

2003-01-01

366

Adaptive HIFU noise cancellation for simultaneous therapy and imaging using an integrated HIFU/imaging transducer  

PubMed Central

It was previously demonstrated that it is feasible to simultaneously perform ultrasound therapy and imaging of a coagulated lesion during treatment with an integrated transducer that is capable of high intensity focused ultrasound (HIFU) and B-mode ultrasound imaging. It was found that coded excitation and fixed notch filtering upon reception could significantly reduce interference caused by the therapeutic transducer. During HIFU sonication, the imaging signal generated with coded excitation and fixed notch filtering had a range side-lobe level of less than ?40 dB, while traditional short-pulse excitation and fixed notch filtering produced a range side-lobe level of ?20 dB. The shortcoming is, however, that relatively complicated electronics may be needed to utilize coded excitation in an array imaging system. It is for this reason that in this paper an adaptive noise canceling technique is proposed to improve image quality by minimizing not only the therapeutic interference, but also the remnant side-lobe ‘ripples’ when using the traditional short-pulse excitation. The performance of this technique was verified through simulation and experiments using a prototype integrated HIFU/imaging transducer. Although it is known that the remnant ripples are related to the notch attenuation value of the fixed notch filter, in reality, it is difficult to find the optimal notch attenuation value due to the change in targets or the media resulted from motion or different acoustic properties even during one sonication pulse. In contrast, the proposed adaptive noise canceling technique is capable of optimally minimizing both the therapeutic interference and residual ripples without such constraints. The prototype integrated HIFU/imaging transducer is composed of three rectangular elements. The 6 MHz center element is used for imaging and the outer two identical 4 MHz elements work together to transmit the HIFU beam. Two HIFU elements of 14.4 mm × 20.0 mm dimensions could increase the temperature of the soft biological tissue from 55 °C to 71 °C within 60 s. Two types of experiments for simultaneous therapy and imaging were conducted to acquire a single scan-line and B-mode image with an aluminum plate and a slice of porcine muscle, respectively. The B-mode image was obtained using the single element imaging system during HIFU beam transmission. The experimental results proved that the combination of the traditional short-pulse excitation and the adaptive noise canceling method could significantly reduce therapeutic interference and remnant ripples and thus may be a better way to implement real-time simultaneous therapy and imaging. PMID:20224162

Jeong, Jong Seob; Cannata, Jonathan Matthew; Shung, K Kirk

2010-01-01

367

The state of the art of adeno-associated virus-based vectors in gene therapy  

Microsoft Academic Search

The adeno-associated virus (AAV) has rapidly gained popularity in gene therapy since the establishment of the first AAV2 infectious clone, in 1982, due to some of their distinguishing characteristics such as lack of pathogenicity, wide range of infectivity, and ability to establish long-term transgene expression. Notably over the past decade, this virus has attracted considerable interest as a gene therapy

Renata dos Santos Coura; Nance Beyer Nardi

2007-01-01

368

Targeted Gene Therapy of Ovarian Cancer Using an Ovarian-Specific Promoter  

Microsoft Academic Search

Objectives. The “suicide” gene therapy of cancer using promoters such as cytomegalovirus could cause severe toxicity to normal tissues due to a lack of specificity of prodrug activation. Therefore, we investigated gene therapy of ovarian cancer using ovarian-specific promoter (OSP1) to limit the synthesis of the prodrug activating enzyme HSVtk to ovarian cancer cells.Methods. The HSVtk expressing plasmid pOSP1–HSVtk was

Rudi Bao; Muthu Selvakumaran; Thomas C. Hamilton

2002-01-01

369

Preclinical evaluation of a class of infectivity-enhanced adenoviral vectors in ovarian cancer gene therapy  

Microsoft Academic Search

Ovarian carcinoma cells are often infected inefficiently by adenoviruses (Ad) due to low expression of coxsackie–adenovirus receptors (CAR), hindering the application of adenovirus-mediated gene therapy in ovarian cancer. In this study, we explored a class of infectivity-enhanced Ad vectors, which contain CAR-independent targeting motifs RGD (Ad5.RGD), polylysine (Ad5.pK7), or both (Ad5.RGD.pK7), for their utility in ovarian cancer gene therapy using

H Wu; T Han; J T Lam; C A Leath; I Dmitriev; E Kashentseva; M N Barnes; R D Alvarez; D T Curiel; DT Curiel

2004-01-01

370

Progress towards liver and lung-directed gene therapy with helper-dependent adenoviral vectors.  

PubMed

Helper-dependent adenoviral vectors (HDAd) have several characteristics making them very attractive for human gene therapy. These vectors are completely devoid of viral coding sequences and are able to mediate high efficiency transduction in vivo to direct high level transgene expression with negligible chronic toxicity. Progress towards liver and lung directed gene therapy with HDAd as well as the current obstacles facing human applications and possible strategies to overcome these obstacles are discussed. PMID:19860648

Brunetti-Pierri, Nicola; Ng, Philip

2009-10-01

371

Gene Therapy in Peripheral Blood Lymphocytes and Bone Marrow for ADA^- Immunodeficient Patients  

Microsoft Academic Search

Adenosine deaminase (ADA) deficiency results in severe combined immunodeficiency, the first genetic disorder treated by gene therapy. Two different retroviral vectors were used to transfer ex vivo the human ADA minigene into bone marrow cells and peripheral blood lymphocytes from two patients undergoing exogenous enzyme replacement therapy. After 2 years of treatment, long-term survival of T and B lymphocytes, marrow

Claudio Bordignon; Luigi D. Notarangelo; Nadia Nobili; Giuliana Ferrari; Giulia Casorati; Paola Panina; Evelina Mazzolari; Daniela Maggioni; Claudia Rossi; Paolo Servida; Alberto G. Ugazio; Fulvio Mavilio

1995-01-01

372

Interferon-? gene therapy improves survival in an immunocompetent mouse model of carcinomatosis  

Microsoft Academic Search

BackgroundInterferon-? (IFN?) has multiple antitumor effects; however, its use has been limited by its short half-life in vivo. This limitation may be overcome by IFN? gene therapy. We evaluated adenovirus-IFN? therapy in an immunocompetent mouse model of carcinomatosis.

Samantha K Hendren; Indira Prabakaran; Donald G Buerk; Giorgos Karakousis; Michael Feldman; Francis Spitz; Chandrakala Menon; Douglas L Fraker

2004-01-01

373

Challenges in image-guided therapy system design.  

PubMed

System development for image-guided therapy (IGT), or image-guided interventions (IGI), continues to be an area of active interest across academic and industry groups. This is an emerging field that is growing rapidly: major academic institutions and medical device manufacturers have produced IGT technologies that are in routine clinical use, dozens of high-impact publications are published in well regarded journals each year, and several small companies have successfully commercialized sophisticated IGT systems. In meetings between IGT investigators over the last two years, a consensus has emerged that several key areas must be addressed collaboratively by the community to reach the next level of impact and efficiency in IGT research and development to improve patient care. These meetings culminated in a two-day workshop that brought together several academic and industrial leaders in the field today. The goals of the workshop were to identify gaps in the engineering infrastructure available to IGT researchers, develop the role of research funding agencies and the recently established US-based National Center for Image Guided Therapy (NCIGT), and ultimately to facilitate the transfer of technology among research centers that are sponsored by the National Institutes of Health (NIH). Workshop discussions spanned many of the current challenges in the development and deployment of new IGT systems. Key challenges were identified in a number of areas, including: validation standards; workflows, use-cases, and application requirements; component reusability; and device interface standards. This report elaborates on these key points and proposes research challenges that are to be addressed by a joint effort between academic, industry, and NIH participants. PMID:17644360

Dimaio, Simon; Kapur, Tina; Cleary, Kevin; Aylward, Stephen; Kazanzides, Peter; Vosburgh, Kirby; Ellis, Randy; Duncan, James; Farahani, Keyvan; Lemke, Heinz; Peters, Terry; Lorensen, William Bill; Gobbi, David; Haller, John; Clarke, Laurence Larry; Pizer, Stephen; Taylor, Russell; Galloway, Robert; Fichtinger, Gabor; Hata, Nobuhiko; Lawson, Kimberly; Tempany, Clare; Kikinis, Ron; Jolesz, Ferenc

2007-01-01

374

Challenges in Image-Guided Therapy System Design  

PubMed Central

System development for Image-Guided Therapy (IGT), or Image-Guided Interventions (IGI), continues to be an area of active interest across academic and industry groups. This is an emerging field that is growing rapidly: major academic institutions and medical device manufacturers have produced IGT technologies that are in routine clinical use, dozens of high-impact publications are published in well regarded journals each year, and several small companies have successfully commercialized sophisticated IGT systems. In meetings between IGT investigators over the last two years, a consensus has emerged that several key areas must be addressed collaboratively by the community to reach the next level of impact and efficiency in IGT research and development to improve patient care. These meetings culminated in a two-day workshop that brought together several academic and industrial leaders in the field today. The goals of the Workshop were to identify gaps in the engineering infrastructure available to IGT researchers, develop the role of research funding agencies and the recently established National Center for Image Guided Therapy (NCIGT), and ultimately to facilitate the transfer of technology among NIH-sponsored research centers. Workshop discussions spanned many of the current challenges in the development and deployment of new IGT systems. Key challenges were identified in a number of areas, including: validation standards; workflows, use-cases and application requirements; component reusability; and device interface standards. This report elaborates on these key points and proposes research challenges that are to be addressed by a joint effort between academic, industry, and NIH participants. PMID:17644360

DiMaio, Simon; Kapur, Tina; Cleary, Kevin; Aylward, Stephen; Kazanzides, Peter; Vosburgh, Kirby; Ellis, Randy; Duncan, Jim; Farahani, Keyvan; Lemke, Heinz; Peters, Terry; Lorensen, Bill; Gobbi, David; Haller, John; Clarke, Larry; Pizer, Steve; Galloway, Bob; Fichtinger, Gabor; Hata, Noby; Lawson, Kim; Tempany, Clare; Kikinis, Ron; Jolesz, Ferenc

2013-01-01

375

Developing protocols for recombinant adeno-associated virus-mediated gene therapy in space.  

PubMed

With the advent of the era of International Space Station (ISS) and Mars exploration, it is important more than ever to develop means to cure genetic and acquired diseases, which include cancer and AIDS, for these diseases hamper human activities. Thus, our ultimate goal is to develop protocols for gene therapy, which are suitable to humans on the earth as well as in space. Specifically, we are trying to cure the hemoglobinopathies, beta-thalassemia (Cooley's anemia) and sickle cell anemia, by gene therapy. These well-characterized molecular diseases serve as models for developing ex vivo gene therapy, which would apply to other disorders as well. For example, the procedure may become directly relevant to treating astronauts for space-anemia, immune suppression and bone marrow derived tumors, e.g. leukemia. The adeno-associated virus serotype 2 (AAV2) is a non-pathogenic human parvovirus with broad host-range and tissue specificity. Exploiting these characteristics we have been developing protocols for recombinant AAV2 (rAAV)-based gene therapy. With the rAAV constructs and hematopoietic stem cell (HSC) culture systems in hand, we are currently attempting to cure the mouse model of beta-thalassemia [C57BL/6- Hbbth/Hbbth, Hb(d-minor)] by HSC transplantation (HST) as well as by gene therapy. This paper describes the current status of our rAAV-gene therapy research. PMID:12697549

Ohi, S

2000-07-01

376

VisANT 4.0: Integrative network platform to connect genes, drugs, diseases and therapies.  

PubMed

With the rapid accumulation of our knowledge on diseases, disease-related genes and drug targets, network-based analysis plays an increasingly important role in systems biology, systems pharmacology and translational science. The new release of VisANT aims to provide new functions to facilitate the convenient network analysis of diseases, therapies, genes and drugs. With improved understanding of the mechanisms of complex diseases and drug actions through network analysis, novel drug methods (e.g., drug repositioning, multi-target drug and combination therapy) can be designed. More specifically, the new update includes (i) integrated search and navigation of disease and drug hierarchies; (ii) integrated disease-gene, therapy-drug and drug-target association to aid the network construction and filtering; (iii) annotation of genes/drugs using disease/therapy information; (iv) prediction of associated diseases/therapies for a given set of genes/drugs using enrichment analysis; (v) network transformation to support construction of versatile network of drugs, genes, diseases and therapies; (vi) enhanced user interface using docking windows to allow easy customization of node and edge properties with build-in legend node to distinguish different node type. VisANT is freely available at: http://visant.bu.edu. PMID:23716640

Hu, Zhenjun; Chang, Yi-Chien; Wang, Yan; Huang, Chia-Ling; Liu, Yang; Tian, Feng; Granger, Brian; Delisi, Charles

2013-07-01

377

Body Image: A Tripartite Model for Use in Dance\\/Movement Therapy  

Microsoft Academic Search

The author presents a theoretical, literature-based study of the body image concept. Conceptualizations of body image in philosophy, psychology, psychiatry, and dance\\/movement therapy are briefly reviewed. A tripartite model for the concept of body image is proposed in order to clarify the meaning of body image. The author differentiates body image into three interrelated aspects: image-properties, body-self, and body-memory. Image-properties

Päivi Pylvänäinen

2003-01-01

378

Gold-silica quantum rattles for multimodal imaging and therapy.  

PubMed

Gold quantum dots exhibit distinctive optical and magnetic behaviors compared with larger gold nanoparticles. However, their unfavorable interaction with living systems and lack of stability in aqueous solvents has so far prevented their adoption in biology and medicine. Here, a simple synthetic pathway integrates gold quantum dots within a mesoporous silica shell, alongside larger gold nanoparticles within the shell's central cavity. This "quantum rattle" structure is stable in aqueous solutions, does not elicit cell toxicity, preserves the attractive near-infrared photonics and paramagnetism of gold quantum dots, and enhances the drug-carrier performance of the silica shell. In vivo, the quantum rattles reduced tumor burden in a single course of photothermal therapy while coupling three complementary imaging modalities: near-infrared fluorescence, photoacoustic, and magnetic resonance imaging. The incorporation of gold within the quantum rattles significantly enhanced the drug-carrier performance of the silica shell. This innovative material design based on the mutually beneficial interaction of gold and silica introduces the use of gold quantum dots for imaging and therapeutic applications. PMID:25653336

Hembury, Mathew; Chiappini, Ciro; Bertazzo, Sergio; Kalber, Tammy L; Drisko, Glenna L; Ogunlade, Olumide; Walker-Samuel, Simon; Krishna, Katla Sai; Jumeaux, Coline; Beard, Paul; Kumar, Challa S S R; Porter, Alexandra E; Lythgoe, Mark F; Boissière, Cédric; Sanchez, Clément; Stevens, Molly M

2015-02-17

379

The potential for gene-targeted radiation therapy of cancers  

Microsoft Academic Search

Targeted cancer therapy is the mantra now chanted by oncologists of all types. Everyone hopes that the rapid expansion in the knowledge of cancer cell genetics, signaling, regulatory factors and other changes that underlie malignant transformation and metastasis will lead to innovative approaches for the treatment of cancers. To date, successful targeted therapies have been derived from pharmaceutical chemistry -

Igor G. Panyutin; Ronald D. Neumann

2005-01-01

380

Gene Therapy Progress and Prospects: Development of improved lentiviral and retroviral vectors – design, biosafety, and production  

Microsoft Academic Search

Replication defective vectors derived from simple retroviruses or the more complex genomes of lentiviruses continue to offer the advantages of long-term expression, cell and tissue specific tropism, and large packaging capacity for the delivery of therapeutic genes. The occurrence of adverse events caused by insertional mutagenesis in three patients in a gene therapy trial for X-linked SCID emphasizes the potential

P L Sinn; S L Sauter; P B McCray

2005-01-01

381

Neonatal Gene Therapy of MPS I Mice by Intravenous Injection of a Lentiviral Vector  

Microsoft Academic Search

Mucopolysaccharidosis type I (MPS I) is a lysosomal glycosaminoglycan (GAG) storage disorder caused by deficiency of ?-L-iduronidase (IDUA). In this study, we evaluated the potential to perform gene therapy for MPS I by direct in vivo injection of a lentiviral vector, using an IDUA gene knockout murine model. We compared the efficacy in newborn versus young adult MPS I mice

Hiroshi Kobayashi; Denise Carbonaro; Karen Pepper; Denise Petersen; Shundi Ge; Holly Jackson; Hiroyuki Shimada; Rex Moats; Donald B. Kohn

2005-01-01

382

Diagnostic test for prenatal identification of Down's syndrome and mental retardation and gene therapy therefor  

DOEpatents

A a diagnostic test useful for prenatal identification of Down syndrome and mental retardation. A method for gene therapy for correction and treatment of Down syndrome. DYRK gene involved in the ability to learn. A method for diagnosing Down's syndrome and mental retardation and an assay therefor. A pharmaceutical composition for treatment of Down's syndrome mental retardation.

Smith, Desmond J. (Oakland, CA); Rubin, Edward M. (Berkeley, CA)

2000-01-01

383

Engineering optically triggered droplets for photoacoustic imaging and therapy  

PubMed Central

Liquid perfluorocarbon (PFC) droplets incorporating optical absorbers can be vaporized through photothermal heating using a pulsed laser source. Here, we report on the effect of droplet core material on the optical fluence required to produce droplet vaporization. We fabricate gold nanoparticle templated microbubbles filled with various PFC gases (C3F8, C4F10, and C5F12) and apply pressure to condense them into droplets. The core material is found to have a strong effect on the threshold optical fluence, with lower boiling point droplets allowing for vaporization at lower laser fluence. The impact of droplet size on vaporization threshold is discussed, as well as a proposed mechanism for the relatively broad distribution of vaporization thresholds observed within a droplet population with the same core material. We propose that the control of optical vaporization threshold enabled by engineering the droplet core may find application in contrast enhanced photoacoustic imaging and therapy. PMID:25574448

Dove, Jacob D.; Mountford, Paul A.; Murray, Todd W.; Borden, Mark A.

2014-01-01

384

Monitoring adenoviral based gene delivery in rat glioma by molecular imaging  

PubMed Central

AIM: To determine whether endothelial progenitor cells (EPCs) can be used as delivery vehicle for adenoviral vectors and imaging probes for gene therapy in glioblastoma. METHODS: To use cord blood derived EPCs as delivery vehicle for adenoviral vectors and imaging probes for glioma gene therapy, a rat model of human glioma was made by implanting U251 cells orthotopically. EPCs were transfected with an adenovirus (AD5/carrying hNIS gene) and labeled with iron oxide and inoculated them directly into the tumor 14 d following implantation of U251 cells. Magnetic resonance imaging (MRI) was used to in vivo track the migration of EPCs in the tumor. The expression of gene products was determined by in vivo Tc-99m single photon emission computed tomography (SPECT). The findings were validated with immunohistochemistry (IHC). RESULTS: EPCs were successfully transfected with the adenoviral vectors carrying hNIS which was proved by significantly (P < 0.05) higher uptake of Tc-99m in transfected cells. Viability of EPCs following transfection and iron labeling was not altered. In vivo imaging showed the presence of iron positive cells and the expression of transgene (hNIS) product on MRI and SPECT, respectively, all over the tumors following administration of transfected and iron labeled EPCs in the tumors. IHC confirmed the distribution of EPC around the tumor away from the injection site and also showed transgene expression in the tumor. The results indicated the EPCs’ ability to deliver adenoviral vectors into the glioma upon intratumor injection. CONCLUSION: EPCs can be used as vehicle to deliver adenoviral vector to glioma and also act as imaging probe at the same time. PMID:24926429

Varma, Nadimpalli Ravi S; Barton, Kenneth N; Janic, Branislava; Shankar, Adarsh; Iskander, ASM; Ali, Meser M; Arbab, Ali S

2013-01-01

385

Gene therapy for carcinoma of the breast: Therapeutic genetic correction strategies  

PubMed Central

Abstract Gene therapy is a therapeutic approach that is designed to correct specific molecular defects that contribute to the cause or progression of cancer. Genes that are mutated or deleted in cancers include the cancer susceptibility genes p53 and BRCA1. Because mutational inactivation of gene function is specific to tumor cells in these settings, cancer gene correction strategies may provide an opportunity for selective targeting without significant toxicity for normal nontumor cells. Both p53 and BRCA1 appear to inhibit cancer cells that lack mutations in these genes, suggesting that the so-called gene correction strategies may have broader potential than initially believed. Increasing knowledge of cancer genetics has identified these and other genes as potential targets for gene replacement therapy. Initial patient trials of p53 and BRCA1 gene therapy have provided some indications of potential efficacy, but have also identified areas of basic and clinical research that are needed before these approaches may be widely used in patient care. PMID:11250690

Obermiller, Patrice S; Tait, David L; Holt, Jeffrey T

2000-01-01

386

Prostate focused ultrasound focal therapy--imaging for the future.  

PubMed

Treatment of prostate cancer using high-intensity focused ultrasound (HIFU) focal therapy will become a reliable treatment option only if several conditions are fulfilled. These conditions concern patient selection, assessment of the tumour location and aggressiveness, evaluation of target tissue destruction, and detection of local recurrence or appearance of new tumours. Regarding patient selection, standard transrectal biopsies are not accurate enough and, although perineal template biopsies can detect tumours, they are invasive, expensive procedures, and there is a risk of incidental detection of insignificant cancers. In turn, multiparametric MRI is accurate for detecting and localizing high-grade (Gleason score ?7) cancers and may provide non-invasive assessment of tumour aggressiveness. Moreover, contrast-enhanced imaging-ultrasonography or MRI-can assess post-HIFU tissue destruction and provide accurate detection of tumour recurrence, which is a key element for follow up. This Perspectives article will assess whether our current methods for cancer diagnosis, tissue targeting, and treatment follow up are accurate enough to allow the design of robust HIFU focal therapy protocols. PMID:22910682

Rouvière, Olivier; Gelet, Albert; Crouzet, Sébastien; Chapelon, Jean-Yves

2012-12-01

387

Current status of gene therapy for breast cancer: progress and challenges.  

PubMed

Breast cancer is characterized by a series of genetic mutations and is therefore ideally placed for gene therapy intervention. The aim of gene therapy is to deliver a nucleic acid-based drug to either correct or destroy the cells harboring the genetic aberration. More recently, cancer gene therapy has evolved to also encompass delivery of RNA interference technologies, as well as cancer DNA vaccines. However, the bottleneck in creating such nucleic acid pharmaceuticals lies in the delivery. Deliverability of DNA is limited as it is prone to circulating nucleases; therefore, numerous strategies have been employed to aid with biological transport. This review will discuss some of the viral and nonviral approaches to breast cancer gene therapy, and present the findings of clinical trials of these therapies in breast cancer patients. Also detailed are some of the most recent developments in nonviral approaches to targeting in breast cancer gene therapy, including transcriptional control, and the development of recombinant, multifunctional bio-inspired systems. Lastly, DNA vaccines for breast cancer are documented, with comment on requirements for successful pharmaceutical product development. PMID:25419154

McCrudden, Cian M; McCarthy, Helen O

2014-01-01

388

Targeted Antiangiogenesis Gene Therapy Using Targeted Cationic Microbubbles Conjugated with CD105 Antibody Compared with Untargeted Cationic and Neutral Microbubbles  

PubMed Central

Objective This study aimed to develop targeted cationic microbubbles conjugated with a CD105 antibody (CMB105) for use in targeted vascular endothelial cell gene therapy and ultrasound imaging. We compared the results with untargeted cationic microbubbles (CMB) and neutral microbubbles (NMB). Methods CMB105 were prepared and compared with untargeted CMB and NMB. First, the microbubbles were characterized in terms of size, zeta-potential, antibody binding ability and plasmid DNA loading capacity. A tumor model of subcutaneous breast cancer in nude mice was used for our experiments. The ability of different types of microbubbles to target HUVECs in vitro and tumor neovascularization in vivo was measured. The endostatin gene was selected for its outstanding antiangiogenesis effect. For in vitro experiments, the transfection efficiency and cell cycle were analyzed using flow cytometry, and the transcription and expression of endostatin were measured by qPCR and Western blotting, respectively. Vascular tube cavity formation and tumor cell invasion were used to evaluate the antiangiogenesis gene therapy efficiency in vitro. Tumors were exposed to ultrasound irradiation with different types of microbubbles, and the gene therapy effects were investigated by detecting apoptosis induction and changes in tumor volume. Results CMB105 and CMB differed significantly from NMB in terms of zeta-potential, and the DNA loading capacities were 16.76±1.75 ?g, 18.21±1.22 ?g, and 0.48±0.04 ?g per 5×108 microbubbles, respectively. The charge coupling of plasmid DNA to CMB105 was not affected by the presence of the CD105 antibody. Both CMB105 and CMB could target to HUVECs in vitro, whereas only CMB105 could target to tumor neovascularization in vivo. In in vitro experiments, the transfection efficiency of CMB105 was 24.7-fold higher than the transfection efficiency of NMB and 1.47-fold higher than the transfection efficiency of CMB (P<0.05). With ultrasound-targeted microbubble destruction (UTMD)-mediated gene therapy, the transcription and expression of endostatin were the highest in the CMB105 group (P<0.001); the antiangiogenesis effect and inhibition of tumor cells invasion was better with CMB105 than CMB or NMB in vitro (P<0.01). After gene therapy, the tumor volumes of CMB105 group were significantly smaller than that of CMB and NMB, and many tumor cells had begun apoptosis in the CMB105 group, which had the highest apoptosis index (P<0.001). Conclusions As a contrast agent and plasmid carrier, CMB105 can be used not only for targeted ultrasound imaging but also for targeted gene therapy both in vitro and in vivo. The plasmid DNA binding ability of the CMB was not affected by conjugation of the CMB with the CD105 antibody, and because of its targeting ability, the gene transfection efficiency and therapeutic effect were better compared with the untargeted CMB and NMB. The advantages of targeted gene therapy with CMB105 in vivo were more prominent than with CMB or NMB because neither can target the endothelia in vivo.

Zhou, Yu; Gu, Haitao; Xu, Yan; Li, Fan; Kuang, Shaojing; Wang, Zhigang; Zhou, Xiyuan; Ma, Huafeng; Li, Pan; Zheng, Yuanyi; Ran, Haitao; Jian, Jia; Zhao, Yajing; Song, Weixiang; Wang, Qiushi; Wang, Dong

2015-01-01

389

Inferring Gene Interaction Networks from ISH Images via Kernelized Graphical Models  

E-print Network

, where each image captures the spatial gene expression pattern of a single gene in the tissue of interest-situ hybridization (ISH) is a newly developed technique that can measure gene expression in tissue without an ontology from images [7], finding related images given an image [8], etc. Reverse engineering gene networks

Xing, Eric P.

390

Sleeping Beauty Transposon System for Genetic Etiological Research and Gene Therapy of Cancers.  

PubMed

Abstract Carcinogenesis is etiologically associated with somatic mutations of critical genes. Recently, a number of somatic mutations and key molecules have been found to be involved in functional networks affecting cancer progression. Suitable animal models are required to validate cancer-promoting or -inhibiting capacities of these mutants and molecules. Sleeping Beauty transposon system consists of a transposon that carries gene(s) of interest and a transposase that recognizes, excises, and reinserts genes in given location of the genome. It can create both gain-of-function and loss-of-function mutations, thus being frequently chosen to investigate the etiological mechanisms and gene therapy for cancers in animal models. In this review, we summarized current advances of Sleeping Beauty transposon system in revealing molecular mechanism of cancers and improving gene therapy. Understanding molecular mechanisms by which driver mutations contribute to carcinogenesis and metastasis may pave the way for the development of innovative prophylactic and therapeutic strategies against malignant diseases. PMID:25455252

Hou, Xiaomei; Du, Yan; Deng, Yang; Wu, Jianfeng; Cao, Guangwen

2014-12-01

391

Segmentation of left atrial intracardiac ultrasound images for image guided cardiac ablation therapy  

NASA Astrophysics Data System (ADS)

Intracardiac echocardiography (ICE), a technique in which structures of the heart are imaged using a catheter navigated inside the cardiac chambers, is an important imaging technique for guidance in cardiac ablation therapy. Automatic segmentation of these images is valuable for guidance and targeting of treatment sites. In this paper, we describe an approach to segment ICE images by generating an empirical model of blood pool and tissue intensities. Normal, Weibull, Gamma, and Generalized Extreme Value (GEV) distributions are fit to histograms of tissue and blood pool pixels from a series of ICE scans. A total of 40 images from 4 separate studies were evaluated. The model was trained and tested using two approaches. In the first approach, the model was trained on all images from 3 studies and subsequently tested on the 40 images from the 4th study. This procedure was repeated 4 times using a leave-one-out strategy. This is termed the between-subjects approach. In the second approach, the model was trained on 10 randomly selected images from a single study and tested on the remaining 30 images in that study. This is termed the within-subjects approach. For both approaches, the model was used to automatically segment ICE images into blood and tissue regions. Each pixel is classified using the Generalized Liklihood Ratio Test across neighborhood sizes ranging from 1 to 49. Automatic segmentation results were compared against manual segmentations for all images. In the between-subjects approach, the GEV distribution using a neighborhood size of 17 was found to be the most accurate with a misclassification rate of approximately 17%. In the within-subjects approach, the GEV distribution using a neighborhood size of 19 was found to be the most accurate with a misclassification rate of approximately 15%. As expected, the majority of misclassified pixels were located near the boundaries between tissue and blood pool regions for both methods.

Rettmann, M. E.; Stephens, T.; Holmes, D. R.; Linte, C.; Packer, D. L.; Robb, R. A.

2013-03-01

392

Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success  

PubMed Central

Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA). Retinal gene therapy restores vision to blind canine and murine models of LCA. Gene therapy in blind humans with LCA from RPE65 mutations may also have potential for success but only if the retinal photoreceptor layer is intact, as in the early-disease stage-treated animals. Here, we use high-resolution in vivo microscopy to quantify photoreceptor layer thickness in the human disease to define the relationship of retinal structure to vision and determine the potential for gene therapy success. The normally cone photoreceptor-rich central retina and rod-rich regions were studied. Despite severely reduced cone vision, many RPE65-mutant retinas had near-normal central microstructure. Absent rod vision was associated with a detectable but thinned photoreceptor layer. We asked whether abnormally thinned RPE65-mutant retina with photoreceptor loss would respond to treatment. Gene therapy in Rpe65-/- mice at advanced-disease stages, a more faithful mimic of the humans we studied, showed success but only in animals with better-preserved photoreceptor structure. The results indicate that identifying and then targeting retinal locations with retained photoreceptors will be a prerequisite for successful gene therapy in humans with RPE65 mutations and in other retinal degenerative disorders now moving from proof-of-concept studies toward clinical trials. PMID:15837919

Jacobson, Samuel G.; Aleman, Tomas S.; Cideciyan, Artur V.; Sumaroka, Alexander; Schwartz, Sharon B.; Windsor, Elizabeth A. M.; Traboulsi, Elias I.; Heon, Elise; Pittler, Steven J.; Milam, Ann H.; Maguire, Albert M.; Palczewski, Krzysztof; Stone, Edwin M.; Bennett, Jean

2005-01-01

393

Gene Therapy for Myocardial Angiogenesis Initial Clinical Results With Direct Myocardial Injection of phVEGF165 as Sole Therapy for Myocardial Ischemia  

Microsoft Academic Search

Background—We initiated a phase 1 clinical study to determine the safety and bioactivity of direct myocardial gene transfer of vascular endothelial growth factor (VEGF) as sole therapy for patients with symptomatic myocardial ischemia. Methods and Results—VEGF gene transfer (GTx) was performed in 5 patients (all male, ages 53 to 71) who had failed conventional therapy; these men had angina (determined

Douglas W. Losordo; Peter R. Vale; James F. Symes; Cheryl H. Dunnington; Darryl D. Esakof; Michael Maysky; Alan B. Ashare; Kishor Lathi; Jeffrey M. Isner

394

Gene therapy for hemoglobinopathies: the state of the field and the future.  

PubMed

After nearly two decades of struggle, gene therapy for hemoglobinopathies using vectors carrying ? or ?-globin gene has finally reached the clinical doorsteps. This was made possible by advances made in our understanding of critical regulatory elements required for high level of globin gene expression and improved gene transfer vectors and methodologies. Development of gene editing technologies and reprogramming somatic cells for regenerative medicine holds the promise of genetic correction of hemoglobinopathies in the future. This article will review the state of the field and the upcoming technologies that will allow genetic therapeutic correction of hemoglobinopathies. PMID:24589262

Chandrakasan, Shanmuganathan; Malik, Punam

2014-04-01

395

Gene therapy approaches for the management of non-small cell lung cancer  

Microsoft Academic Search

Targeting the specific genetic lesions responsible for carcinogenesis and cancer progression is an attractive strategy for developing more effective anticancer therapies and reducing treatment-related toxicity. The restoration of defective tumor suppressor gene pathways by replacement of tumor suppressor genes in cancer cells has been studied in lung cancer. The most extensively studied agent is the wild-type p53 tumor suppressor gene

Jack A Roth; Susan F Grammer; Stephen G Swisher; Ritsuko Komaki; John Nemunaitis; James Merritt; Toshiyoshi Fujiwara; Raymond E Meyn

2001-01-01

396

Utilizing Social Media to Study Information-Seeking and Ethical Issues in Gene Therapy  

PubMed Central

Background The field of gene therapy is rapidly evolving, and while hopes of treating disorders of the central nervous system and ethical concerns have been articulated within the academic community, little is known about views and opinions of different stakeholder groups. Objective To address this gap, we utilized social media to investigate the kind of information public users are seeking about gene therapy and the hopes, concerns, and attitudes they express. Methods We conducted a content analysis of questions containing the keywords “gene therapy” from the Q&A site “Yahoo! Answers” for the 5-year period between 2006 and 2010. From the pool of questions retrieved (N=903), we identified those containing at least one theme related to ethics, environment, economics, law, or society (n=173) and then characterized the content of relevant answers (n=399) through emergent coding. Results The results show that users seek a wide range of information regarding gene therapy, with requests for scientific information and ethical issues at the forefront of enquiry. The question sample reveals high expectations for gene therapy that range from cures for genetic and nongenetic diseases to pre- and postnatal enhancement of physiological attributes. Ethics questions are commonly expressed as fears about the impact of gene therapy on self and society. The answer sample echoes these concerns but further suggests that the acceptability of gene therapy varies depending on the specific application. Conclusions Overall, the findings highlight the powerful role of social media as a rich resource for research into attitudes toward biomedicine and as a platform for knowledge exchange and public engagement for topics relating to health and disease. PMID:23470490

Robillard, Julie M; Whiteley, Louise; Johnson, Thomas Wade; Lim, Jonathan; Wasserman, Wyeth W

2013-01-01

397

Theranostic Studies of Human Sodium Iodide Symporter Imaging and Therapy Using 188Re: A Human Glioma Study in Mice  

PubMed Central

Objective To investigate the role of 188Re in human sodium iodide symporter (hNIS) theranostic gene-mediated human glioma imaging and therapy in model mice. Methods The human glioma cell line U87 was transfected with recombinant lentivirus encoding the hNIS gene under the control of cytomegalovirus promoter (U87-hNIS). The uptake and efflux of 188Re were determined after incubating the cells with 188Re. 188Re uptake experiments in the presence of various concentrations of sodium perchlorate were carried out. In vitro cell killing tests with 188Re were performed. U87-hNIS mediated 188Re distribution, imaging and therapy in nude mice were also tested. Results U87-hNIS cell line was successfully established. The uptake of 188Re in U87-hNIS cells increased up to 26-fold compared to control cells, but was released rapidly with a half-life of approximately 4 minutes. Sodium perchlorate reduced hNIS-mediated 188Re uptake to levels of control cell lines. U87-hNIS cells were selectively killed following exposure to 188Re, with a survival of 21.4%, while control cells had a survival of 92.1%. Unlike in vitro studies, U87-hNIS tumor showed a markedly increased 188Re retention even 48 hours after 188Re injection. In the therapy study, there was a significant difference in tumor size between U87-hNIS mice (317±67 mm3) and control mice (861±153 mm3) treated with 188Re for 4 weeks (P<0.01). Conclusion The results indicate that inserting the hNIS gene into U87 cells is sufficient to induce specific 188Re uptake, which has a cell killing effect both in vitro and in vivo. Moreover, our study, based on the function of hNIS as a theranostic gene allowing noninvasive imaging of hNIS expression by 188Re scintigraphy, provides detailed characterization of in vivo vector biodistribution and level, localization, essential prerequisites for precise planning and monitoring of clinical gene therapy that aims to individualize gene therapy concept. PMID:25000403

Guo, Rui; Zhang, M.; Xi, Yun; Ma, Yufei; Liang, Sheng; Shi, Shuo; Miao, Ying; Li, Biao

2014-01-01

398

Lymphocytes as cellular vehicles for gene therapy in mouse and man  

SciTech Connect

The application of bone marrow gene therapy has been stalled by the inability to achieve stable high-level gene transfer and expression in the totipotent stem cells. The authors that retroviral vectors can stably introduce genes into antigen-specific murine and human T lymphocytes in culture. Murine helper T cells were transduced with the retroviral vector SAX to express both neomycin-resistance and human adenosine deaminase genes. To determine if cultured T cells might be used for gene therapy, their persistence and continued expression of the introduced genes was evaluated in nude mice transplanted with the SAX-transduced T cells. They studied cultured human tumor-infiltrating lymphocytes as a candidate cell for a trial of gene transfer in man. Gene insertion and subsequent G418 selection did not substantially alter the growth characteristics, interleukin 2 dependence, membrane phenotype, or cytotoxicity profile of the transduced T cells. These studies provided a portion of the experimental evidence supporting the feasibility of the presently ongoing clinical trials of lymphocyte gene therapy in cancer as well as in patients with adenosine deaminase deficiency.

Culver, K.; Cornetta, K.; Morgan, R.; Morecki, S.; Aebersold, P.; Kasid, A.; Lotze, M.; Rosenberg, S.A.; Anderson, W.F.; Blaese, R.M. (National Inst. of Health, Bethesda, MD (United States))

1991-04-15

399

Kalman Filtered MR Temperature Imaging for Laser Induced Thermal Therapies  

PubMed Central

The feasibility of using a stochastic form of Pennes bioheat model within a 3D finite element based Kalman filter (KF) algorithm is critically evaluated for the ability to provide temperature field estimates in the event of magnetic resonance temperature imaging (MRTI) data loss during laser induced thermal therapy (LITT). The ability to recover missing MRTI data was analyzed by systematically removing spatiotemporal information from a clinical MR-guided LITT procedure in human brain and comparing predictions in these regions to the original measurements. Performance was quantitatively evaluated in terms of a dimensionless L2 (RMS) norm of the temperature error weighted by acquisition uncertainty. During periods of no data corruption, observed error histories demonstrate that the Kalman algorithm does not alter the high quality temperature measurement provided by MR thermal imaging. The KF-MRTI implementation considered is seen to predict the bioheat transfer with RMS error < 4 for a short period of time, ?t < 10sec, until the data corruption subsides. In its present form, the KF-MRTI method currently fails to compensate for consecutive for consecutive time periods of data loss ?t > 10sec. PMID:22203706

Fuentes, D.; Yung, J.; Hazle, J. D.; Weinberg, J. S.; Stafford, R. J.

2013-01-01

400

Ferritin reporter used for gene expression imaging by magnetic resonance  

SciTech Connect

Magnetic resonance imaging (MRI) is a minimally invasive way to provide high spatial resolution tomograms. However, MRI has been considered to be useless for gene expression imaging compared to optical imaging. In this study, we used a ferritin reporter, binding with biogenic iron, to make it a powerful tool for gene expression imaging in MRI studies. GL261 mouse glioma cells were over-expressed with dual-reporter ferritin-DsRed under {beta}-actin promoter, then gene expression was observed by optical imaging and MRI in a brain tumor model. GL261 cells expressing ferritin-DsRed fusion protein showed enhanced visualizing effect by reducing T2-weighted signal intensity for in vitro and in vivo MRI studies, as well as DsRed fluorescence for optical imaging. Furthermore, a higher contrast was achieved on T2-weighted images when permeating the plasma membrane of ferritin-DsRed-expressing GL261. Thus, a ferritin expression vector can be used as an MRI reporter to monitor in vivo gene expression.

Ono, Kenji; Fuma, Kazuya; Tabata, Kaori [Department of Brain Functions, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601 (Japan)] [Department of Brain Functions, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601 (Japan); Sawada, Makoto, E-mail: msawada@riem.nagoya-u.ac.jp [Department of Brain Functions, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601 (Japan)] [Department of Brain Functions, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601 (Japan)

2009-10-23

401

New gene therapy strategies for cancer treatment: a review of recent patents.  

PubMed

Cancer is the second leading cause of death in the Western world. The limited successes of available treatments for cancer mean that new strategies need to be developed. The possibility of modifying the cancer cell with the introduction of genetic material opens the way to a new approach based on gene therapy. There are still many technical difficulties to be overcome, but recent advances in the molecular and cellular biology of gene transfer have made it likely that gene therapy will soon start to play an increasing role in clinical practice, particularly in the treatment of cancer. Gene therapy will probably be the therapeutic option in cases in which conventional treatments such as surgery, radiotherapy and chemotherapy have failed. The development of modified vectors, and an improved understanding of interactions between the vector and the human host, are generating inventions that are being protected by patents due to the considerable interest of industry for their possible commercialization. We review the latest strategies, patented and/or under clinical trial, in cancer gene therapy. These include patents that cover the use of modified vectors to increase the security and specificity, recombining adenovirus that leads to loss or gain of gene function, activation of the patient's own immune cells to eliminate cancer cells by expression of molecules that enhance immune responses, silencing genes related to the development of drug resistance in patients, inhibition of angiogenesis of solid tumors by targeting the tumor vasculature, and the development of enzymes that destroy viral or cancerous genetic material. PMID:22339358

Ortiz, Raúl; Melguizo, Consolación; Prados, José; Álvarez, Pablo J; Caba, Octavio; Rodríguez-Serrano, Fernando; Hita, Fidel; Aránega, Antonia

2012-09-01

402

Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferon? therapy in multiple sclerosis.  

PubMed

Interferon-? (IFN?) therapy is effective in approximately half of the patients with relapsing-remitting multiple sclerosis (RRMS). Clinical non-responders were characterized by an increased expression of IFN response genes before the start of therapy, and a lack of a pharmacologically induced increase in IFN response gene activity. Because Interferon Regulatory Factor 5 (IRF5) is a master regulator of IFN-activity, we carried out a candidate gene study of IRF5 gene variants in relation to the pharmacological and clinical response upon IFN? treatment. We found that patients with the IRF5 rs2004640-TT and rs47281420-AA genotype exerted a poor pharmacological response to IFN? compared with patients carrying the respective G-alleles (P=0.0006 and P=0.0023, respectively). Moreover, patients with the rs2004640-TT genotype developed more magnetic resonance imaging (MRI)-based T2 lesions during IFN? treatment (P=0.003). Accordingly, an association between MRI-based non-responder status and rs2004640-TT genotype was observed (P=0.010). For the rs4728142-AA genotype a trend of an association with more T2 lesions during IFN? treatment and MRI-based non-responder status was observed (P=0.103 and P=0.154, respectively). The clinical relevance of the rs2004640-TT genotype was validated in an independent cohort wherein a shorter time to first relapse was found (P=0.037). These findings suggest a role for IRF5 gene variation in the pharmacological and clinical outcome of IFN? therapy that might have relevance as biomarker to predict the response to IFN? in multiple sclerosis. PMID:21471993

Vosslamber, S; van der Voort, L F; van den Elskamp, I J; Heijmans, R; Aubin, C; Uitdehaag, B M J; Crusius, J B A; van der Pouw Kraan, T C T M; van der PouwKraan, T C T M; Comabella, M; Montalban, X; Hafler, D A; De Jager, P L; Killestein, J; Polman, C H; Verweij, C L

2011-09-01

403

Radiosynthesis of 4-[(2-chloroethyl)(2-[(11)C]ethyl)amino]-phenoxycarbonyl-l-glutamic acid a half mustard prodrug as a potential probe for imaging antibody- and gene-directed enzyme prodrug therapy with positron emission tomography.  

PubMed

The potential antibody directed prodrug therapy half-mustard prodrug 4-[(2-chloroethyl)(2-ethyl)amino]-phenoxycarbonyl-L-glutamic acid was synthesised by reductive alkylation of 4-[(2-chloroethyl)amino]-phenoxycarbonyl-L-glutamic acid using acetaldehyde. 4-[(2-chloroethyl)[(11)C](2-ethyl)amino]phenoxycarbonyl-L-glutamic acid was synthesized with 18-22% decay corrected radiochemical yield in 45 min from EOB by reductive alkylation of 4-[(2-chloroethyl)amino]-phenoxycarbonyl-L-glutamic acid using [(11)C]acetaldehyde. [(11)C]Acetaldehyde was prepared in 60% decay corrected radiochemical yield by oxidation of [(11)C]ethanol over heated copper oxide. The radiosynthesis of [(11)C]ethanol was re-examined and optimized. 4-[(2-chloroethyl)(2-ethyl)amino]-phenoxycarbonyl-L-glutamic acid was found to have affinity for carboxypeptidase G2; the K(m) and V(max) were 99.4-115.9 microM (n=3) and 3.6-5.0 microM/min, respectively, at a carboxypeptidase G2 concentration of 0.0247 U/ml. PMID:15110346

Malik, Nazreen; Luthra, S K Sajinder K; Burke, Phil; Price, P M Patrica M; Aboagye, E O Eric O; Latigo, John; Zhao, Yongjun; Brady, Frank

2004-06-01

404

Combination gene therapy targeting on interleukin-1? and RANKL for wear debris-induced aseptic loosening.  

PubMed

This study investigated the efficacy of a combination gene therapy to repress interleukin-1 (IL-1) and receptor activator of nuclear factor NF-kappa B ligand (RANKL) for the treatment of particulate debris-induced aseptic loosening, and tried to explore the molecular mechanism of the exogenous gene modifications on osteoclastogenesis. RAW cells activated by titanium particles were transduced with DFG-IL-1Ra (retroviral vector encoding IL-1 receptor antagonist) and AAV-OPG (adeno-associated viral vectors-osteoprotegerin) individually or in combination for 4 weeks. Pro-inflammatory cytokines in culture media were determined by enzyme-linked immunosorbent assay, and gene expressions of RANK, IL-1?, c-Fos, TRAF6, JNK1 and CPK were examined using real-time PCR. An established knee-implant-failure mouse model was employed to evaluate the efficacy of the in vivo double-gene therapy. The surgical implantation of a titanium alloy pin into the proximal tibia was followed by monthly challenge with titanium debris. Peri-implant gene transfers of IL-1Ra and OPG (respectively or in combination) were given 3 weeks after surgery. The combination of OPG and IL-1Ra gene transfer exhibited strong synergetic effects in blockage of inflammation and osteoclastogenesis at 8 weeks after gene modification. The combination therapy reversed peri-implant bone resorption and restored implant stability when compared with either single gene transduction. Real-time PCR data indicated that the action of IL-1Ra gene therapy may be mediated via the JNK1 pathway, while the reduction of osteoclastogenesis by OPG gene modification may be regulated by c-Fos expression. In addition, both gene modifications resulted in significant diminishment of TRAF6 expression. PMID:22318091

Wang, H; Jia, T-H; Zacharias, N; Gong, W; Du, H-X; Wooley, P H; Yang, S-Y

2013-02-01

405

Nanoparticles for biomedical imaging, therapy, and quantitative diagnostics  

NASA Astrophysics Data System (ADS)

Nanoparticles and nanomaterials are known to exhibit extraordinary characteristics and have a wide range of application which utilizes their unique properties. In particular, nanoparticles have shown great promise towards advancing the state of biological and biomedical techniques such as in vivo and in vitro imaging modalities, biosensing, and disease detection and therapy. Nanocrystalline hosts: NaYF4, KYF4, KGdF4, NaMF3, and KMF3 (M=Mg, Ba, Mn, Fe, Co, Ni, Cr) doped with rare earth ions have been synthesized by thermolysis, solvothermal, and hydrothermal methods. The morphology and spectroscopic properties have been thoroughly characterized. These nanoparticles (NP) are particularly useful for biomedical purposes since both the exciting and emitting wavelengths are in the near-infrared, where most tissues do not strongly absorb or scatter light. In vivo and in vitro imaging was performed with a 980 nm excitation source. Finally, NPs were conjugated with zinc phthalocyanine, a photosensitizer with a large absorption coefficient in the red and NIR regions, to illustrate the efficacy of these NPs as a platform for dual-mode infrared-activated imaging and photodynamic platforms. In addition, nonlinear optical nanomaterials, such as BaTiO3 and Ag@BaTiO3, were also synthesized and characterized. The nonlinear optical properties were investigated, and it is demonstrated that these nanoparticles can produce phase conjugate waves when used in a counterpropagating four wave mixing setup. The third order susceptibility is quantified using the z-scan technique, and the toxicity of these nanoparticles is also explored.

Yust, Brian G.

406

H U M A N GENE THERAPY 4:759-769 (1993) Mary Ann Liebert, Inc., Publishers  

E-print Network

H U M A N GENE THERAPY 4:759-769 (1993) Mary Ann Liebert, Inc., Publishers A d e n o v i r u s - M efficacy of El-deleted adenoviruses in baboons for lung-directed gene therapy of cystic fibrosis (CF). T h for gene therapies of lung disease in cystic fibrosis (CF). A n evaluation of the feasibility and safety

Engelhardt, John F.

407

How to overcome (and exploit) tumor hypoxia for targeted gene therapy.  

PubMed

Tumor hypoxia has long been recognized as a critical issue in oncology. Resistance of hypoxic areas has been shown to affect treatment outcome after radiation, chemotherapy, and surgery in a number of tumor sites. Two main strategies to overcome tumor hypoxia are to increase the delivery of oxygen (or oxygen-mimetic drugs), and exploiting this unique environmental condition of solid tumors for targeted therapy. The first strategy includes hyperbaric oxygen breathing, the administration of carbogen and nicotinamide, and the delivery of chemical radiosensitizers. In contrast, bioreductive drugs and hypoxia-targeted suicide gene therapy aim at activating cytotoxic agents at the tumor site, while sparing normal tissue from damage. The cellular machinery responds to hypoxia by activating the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. In most cases, transcription is initiated by the binding of the transcription factor hypoxia-inducible factor (HIF) to hypoxia responsive elements (HREs). Hypoxia-targeting for gene therapy has been achieved by utilizing promoters containing HREs, to induce selective and efficient transgene activation at the tumor site. Hypoxia-targeted delivery and prodrug activation may add additional levels of selectivity to the treatment. In this article, the latest developments of cancer gene therapy of the hypoxic environment are discussed, with particular attention to combined protocols with ionizing radiation. Ultimately, it is proposed that by adopting specific transgene activation and molecular amplification systems, resistant hypoxic tumor tissues may be effectively targeted with gene therapy. PMID:14566961

Greco, Olga; Marples, Brian; Joiner, Michael C; Scott, Simon D

2003-12-01

408

Citation: Molecular TherapyNucleic Acids (2013) 2, e68; doi:10.1038/mtna.2012.55 2013 American Society of Gene & Cell Therapy All rights reserved 2158-3188/11  

E-print Network

Society of Gene & Cell Therapy All rights reserved 2158-3188/11 www.nature.com/mtna 1 Centre hospitalier-mail: christian.beausejour@recherche-ste-justine.qc.ca Keywords: dystrophin; gene addition; gene therapy; myoblast.Most current gene therapy pro- tocols aiming to achieve long-term expression of a therapeu- tic transgene rely

Cai, Long

409

Rational design of a triple reporter gene for multimodality molecular imaging.  

PubMed

Multimodality imaging using noncytotoxic triple fusion (TF) reporter genes is an important application for cell-based tracking, drug screening, and therapy. The firefly luciferase (fl), monomeric red fluorescence protein (mrfp), and truncated herpes simplex virus type 1 thymidine kinase SR39 mutant (ttksr39) were fused together to create TF reporter gene constructs with different order. The enzymatic activities of TF protein in vitro and in vivo were determined by luciferase reporter assay, H-FEAU cellular uptake experiment, bioluminescence imaging, and micropositron emission tomography (microPET). The TF construct expressed in H1299 cells possesses luciferase activity and red fluorescence. The tTKSR39 activity is preserved in TF protein and mediates high levels of H-FEAU accumulation and significant cell death from ganciclovir (GCV) prodrug activation. In living animals, the luciferase and tTKSR39 activities of TF protein have also been successfully validated by multimodality imaging systems. The red fluorescence signal is relatively weak for in vivo imaging but may expedite FACS-based selection of TF reporter expressing cells. We have developed an optimized triple fusion reporter construct DsRedm-fl-ttksr39 for more effective and sensitive in vivo animal imaging using fluorescence, bioluminescence, and PET imaging modalities, which may facilitate different fields of biomedical research and applications. PMID:24809057

Hsieh, Ya-Ju; Hwu, Luen; Ke, Chien-Chih; Yeh, Skye Hsin-Hsien; Lin, Chien-Feng; Chen, Fu-Du; Wang, Hsin-Ell; Lin, Kang-Ping; Chen, Ran-Chou; Liu, Ren-Shyan

2014-01-01

410

Spatially weighted mutual information image registration for image guided radiation therapy  

SciTech Connect

Purpose: To develop a new metric for image registration that incorporates the (sub)pixelwise differential importance along spatial location and to demonstrate its application for image guided radiation therapy (IGRT). Methods: It is well known that rigid-body image registration with mutual information is dependent on the size and location of the image subset on which the alignment analysis is based [the designated region of interest (ROI)]. Therefore, careful review and manual adjustments of the resulting registration are frequently necessary. Although there were some investigations of weighted mutual information (WMI), these efforts could not apply the differential importance to a particular spatial location since WMI only applies the weight to the joint histogram space. The authors developed the spatially weighted mutual information (SWMI) metric by incorporating an adaptable weight function with spatial localization into mutual information. SWMI enables the user to apply the selected transform to medically ''important'' areas such as tumors and critical structures, so SWMI is neither dominated by, nor neglects the neighboring structures. Since SWMI can be utilized with any weight function form, the authors presented two examples of weight functions for IGRT application: A Gaussian-shaped weight function (GW) applied to a user-defined location and a structures-of-interest (SOI) based weight function. An image registration example using a synthesized 2D image is presented to illustrate the efficacy of SWMI. The convergence and feasibility of the registration method as applied to clinical imaging is illustrated by fusing a prostate treatment planning CT with a clinical cone beam CT (CBCT) image set acquired for patient alignment. Forty-one trials are run to test the speed of convergence. The authors also applied SWMI registration using two types of weight functions to two head and neck cases and a prostate case with clinically acquired CBCT/MVCT image sets. The SWMI registration with a Gaussian weight function (SWMI-GW) was tested between two different imaging modalities: CT and MRI image sets. Results: SWMI-GW converges 10% faster than registration using mutual information with an ROI. SWMI-GW as well as SWMI with SOI-based weight function (SWMI-SOI) shows better compensation of the target organ's deformation and neighboring critical organs' deformation. SWMI-GW was also used to successfully fuse MRI and CT images. Conclusions: Rigid-body image registration using our SWMI-GW and SWMI-SOI as cost functions can achieve better registration results in (a) designated image region(s) as well as faster convergence. With the theoretical foundation established, we believe SWMI could be extended to larger clinical testing.

Park, Samuel B.; Rhee, Frank C.; Monroe, James I.; Sohn, Jason W. [Department of Radiation Oncology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106 (United States); School of Electrical Engineering and Computer Science, Hanyang University, 1271 Sangrok-gu Sa-3-dong, Ansan, Gyeonggi 426-791 (Korea, Republic of); Medical Physics Services Ltd., 430 Saddlespur Road, Webster Groves, Missouri 63119 (United States); Department of Radiation Oncology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106 (United States)

2010-09-15

411

A knowledge-based imaging informatics approach to managing patients treated with proton beam therapy  

Microsoft Academic Search

Last year we presented work on an imaging informatics approach towards developing quantitative knowledge and tools based on standardized DICOM-RT objects for Image-Guided Radiation Therapy. In this paper, we have extended this methodology to perform knowledge-based medical imaging informatics research on specific clinical scenarios where brain tumor patients are treated with Proton Beam Therapy (PT). PT utilizes energized charged particles,

B. J. Liu; H. K. Huang; M. Law; Anh Le; Jorge Documet; Arek Gertych

2007-01-01

412

Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy.  

PubMed

The use of adeno-associated virus (AAV) as a gene therapy vector has been approved recently for clinical use and has demonstrated efficacy in a growing number of clinical trials. However, the safety of AAV as a vector has been challenged by a single study that documented hepatocellular carcinoma (HCC) after AAV gene delivery in mice. Most studies have not noted genotoxicity following AAV-mediated gene delivery; therefore, the possibility that there is an association between AAV and HCC is controversial. Here, we performed a comprehensive study of HCC in a large number of mice following therapeutic AAV gene delivery. Using a sensitive high-throughput integration site-capture technique and global expressional analysis, we found that AAV integration into the RNA imprinted and accumulated in nucleus (Rian) locus, and the resulting overexpression of proximal microRNAs and retrotransposon-like 1 (Rtl1) were associated with HCC. In addition, we demonstrated that the AAV vector dose, enhancer/promoter selection, and the timing of gene delivery are all critical factors for determining HCC incidence after AAV gene delivery. Together, our results define aspects of AAV-mediated gene therapy that influence genotoxicity and suggest that these features should be considered for design of both safer AAV vectors and gene therapy studies. PMID:25607839

Chandler, Randy J; LaFave, Matthew C; Varshney, Gaurav K; Trivedi, Niraj S; Carrillo-Carrasco, Nuria; Senac, Julien S; Wu, Weiwei; Hoffmann, Victoria; Elkahloun, Abdel G; Burgess, Shawn M; Venditti, Charles P

2015-02-01

413

Monitoring proton radiation therapy with in-room PET imaging  

NASA Astrophysics Data System (ADS)

We used a mobile positron emission tomography (PET) scanner positioned within the proton therapy treatment room to study the feasibility of proton range verification with an in-room, stand-alone PET system, and compared with off-line equivalent studies. Two subjects with adenoid cystic carcinoma were enrolled into a pilot study in which in-room PET scans were acquired in list-mode after a routine fractionated treatment session. The list-mode PET data were reconstructed with different time schemes to generate in-room short, in-room long and off-line equivalent (by skipping coincidences from the first 15 min during the list-mode reconstruction) PET images for comparison in activity distribution patterns. A phantom study was followed to evaluate the accuracy of range verification for different reconstruction time schemes quantitatively. The in-room PET has a higher sensitivity compared to the off-line modality so that the PET acquisition time can be greatly reduced from 30 to <5 min. Features in deep-site, soft-tissue regions were better retained with in-room short PET acquisitions because of the collection of 15O component and lower biological washout. For soft tissue-equivalent material, the distal fall-off edge of an in-room short acquisition is deeper compared to an off-line equivalent scan, indicating a better coverage of the high-dose end of the beam. In-room PET is a promising low cost, high sensitivity modality for the in vivo verification of proton therapy. Better accuracy in Monte Carlo predictions, especially for biological decay modeling, is necessary.

Zhu, Xuping; España, Samuel; Daartz, Juliane; Liebsch, Norbert; Ouyang, Jinsong; Paganetti, Harald; Bortfeld, Thomas R.; El Fakhri, Georges

2011-07-01

414

Monitoring proton radiation therapy with in-room PET imaging  

PubMed Central

Purpose We used a mobile PET scanner positioned within the proton therapy treatment room to study the feasibility of proton range verification with an in-room, stand-alone PET system, and compared with off-line equivalent studies. Methods and materials Two subjects with adenoid cystic carcinoma were enrolled into a pilot study in which in-room PET scans were acquired in list-mode after a routine fractionated treatment session. The list-mode PET data were reconstructed with different time schemes to generate in-room short, in-room long and off-line equivalent (by skipping coincidences from the first 15 minutes during the list-mode reconstruction) PET images for comparison in activity distribution patterns. A phantom study was followed to evaluate the accuracy of range verification for different reconstruction time schemes quantitatively. Results The in-room PET has a higher sensitivity compared to the off-line modality so that the PET acquisition time can be greatly reduced from 30 min to <5 min. Features in deep-site, soft-tissue regions were better retained with in-room short PET acquisitions because of the collection of 15O component and lower biological washout. For soft tissue-equivalent material, the distal fall-off edge of an in-room short acquisition is deeper compared to an off-line equivalent scan, indicating a better coverage of the high-dose end of the beam. Conclusions In-room PET is a promising low cost, high sensitivity modality for the in vivo verification of proton therapy. Better accuracy in Monte Carlo predictions, especially for biological decay modeling, is necessary. PMID:21677366

Zhu, Xuping; España, Samuel; Daartz, Juliane; Liebsch, Norbert; Ouyang, Jinsong; Paganetti, Harald; Bortfeld, Thomas R; El Fakhri, Georges

2011-01-01

415

Targeting of adenoviral vectors for gene therapy of prostate cancer  

Microsoft Academic Search

The transduction of cytotoxic genes by adenoviral vectors into prostatic cells offers a new entity for the treatment of prostate cancer. Current adenoviral vectors cannot infect prostatic cells selectively, and expression of therapeutic genes is often too low to be efficient. Bispecific antibodies may alter the natural tropism of adenoviral vectors towards prostatic cells, and increase the efficacy of infection

CH Bangma

2000-01-01

416

Immune response to green fluorescent protein: implications for gene therapy  

Microsoft Academic Search

Green fluorescent protein (GFP) is a widely used intracellular reporter molecule to assess gene transfer and expression. A potential use for GFP is as a co-expressed marker, to select and enrich gene-modified cells by flow cytometry. Processed peptides derived from GFP and presented by the major histocompatibility complex on the cell surface could potentially induce T cell immune responses against

R Stripecke; M del Carmen Villacres; D C Skelton; N Satake; S Halene; D B Kohn

1999-01-01

417

PTTG: an important target gene for ovarian cancer therapy  

Microsoft Academic Search

Pituitary tumor transforming gene (PTTG), also known as securin is an important gene involved in many biological functions including inhibition of sister chromatid separation, DNA repair, organ development, and expression and secretion of angiogenic and metastatic factors. Proliferating cancer cells and most tumors express high levels of PTTG. Overexpression of PTTG in vitro induces cellular transformation and development of tumors

Siva Kumar Panguluri; Casey Yeakel; Sham S Kakar

2008-01-01

418

Simian virus 40 vectors for pulmonary gene therapy  

Microsoft Academic Search

BACKGROUND: Sepsis remains the leading cause of death in critically ill patients. One of the primary organs affected by sepsis is the lung, presenting as the Acute Respiratory Distress Syndrome (ARDS). Organ damage in sepsis involves an alteration in gene expression, making gene transfer a potential therapeutic modality. This work examines the feasibility of applying simian virus 40 (SV40) vectors

Luminita Eid; Zohar Bromberg; Mahmoud Abd EL-Latif; Evelyn Zeira; Ariella Oppenheim; Yoram G Weiss

2007-01-01

419

Image-Guided Radiation Therapy: the potential for imaging science research to improve cancer treatment outcomes  

NASA Astrophysics Data System (ADS)

The role of medical imaging in the planning and delivery of radiation therapy (RT) is rapidly expanding. This is being driven by two developments: Image-guided radiation therapy (IGRT) and biological image-based planning (BIBP). IGRT is the systematic use of serial treatment-position imaging to improve geometric targeting accuracy and/or to refine target definition. The enabling technology is the integration of high-performance three-dimensional (3D) imaging systems, e.g., onboard kilovoltage x-ray cone-beam CT, into RT delivery systems. IGRT seeks to adapt the patient's treatment to weekly, daily, or even real-time changes in organ position and shape. BIBP uses non-anatomic imaging (PET, MR spectroscopy, functional MR, etc.) to visualize abnormal tissue biology (angiogenesis, proliferation, metabolism, etc.) leading to more accurate clinical target volume (CTV) delineation and more accurate targeting of high doses to tissue with the highest tumor cell burden. In both cases, the goal is to reduce both systematic and random tissue localization errors (2-5 mm for conventional RT) conformality so that planning target volume (PTV) margins (varying from 8 to 20 mm in conventional RT) used to ensure target volume coverage in the presence of geometric error, can be substantially reduced. Reduced PTV expansion allows more conformal treatment of the target volume, increased avoidance of normal tissue and potential for safe delivery of more aggressive dose regimens. This presentation will focus on the imaging science challenges posed by the IGRT and BIBP. These issues include: Development of robust and accurate nonrigid image-registration (NIR) tools: Extracting locally nonlinear mappings that relate, voxel-by-voxel, one 3D anatomic representation of the patient to differently deformed anatomies acquired at different time points, is essential if IGRT is to move beyond simple translational treatment plan adaptations. NIR is needed to map segmented and labeled anatomy from the pretreatment planning images to each daily treatment position image and to deformably map delivered dose distributions computed on each time instance of deformed anatomy, back to the reference 3D anatomy. Because biological imaging must be performed offline, NIR is needed to deformably map these images onto CT images acquired during treatment. Reducing target and organ contouring errors: As IGRT significantly reduces impact of differences between planning and treatment anatomy, RT targeting accuracy becomes increasingly dominated by the remaining systematic treatment-preparation errors, chiefly error in delineating the clinical target volume (CTV) and organs-at-risk. These delineation errors range from 1 mm to 5 mm. No single solution to this problem exists. For BIBP, a better understanding of tumor cell density vs. signal intensity is required. For anatomic CT imaging, improved image reconstruction techniques that improve contrast-to-noise ratio, reduce artifacts due to limited projection data, and incorporate prior information are promising. More sophisticated alternatives to the current concept fixed boundary anatomic structures are needed, e.g., probabilistic CTV representations that incorporate delineation uncertainties. Quantifying four-dimensional (4D) anatomy: For adaptive treatment planning to produce an optimal time sequence of delivery parameters, a 4D anatomic representation, the spatial trajectory through time of each tissue voxel, is needed. One approach is to use sequences of deformation vector fields derived by non-rigidly registering each treatment image to the reference planning CT. One problem to be solved is prediction of future deformed anatomies from past behavior so that time delays inherent in any adaptive replanning feedback loop can be overcome. Another unsolved problem is quantification 4D anatomy uncertainties and how to incorporate such uncertainties into the treatment planning process to avoid geometric ``miss'' of the target tissue.

Williamson, Jeffrey

2008-03-01

420

Understanding risk for psychopathology through imaging gene-environment interactions  

PubMed Central

Examining the interplay of genes, experience, and the brain is critical to understanding psychopathology. We review the recent gene-environment interaction (GxE) and imaging genetics literature with the goal of developing models to bridge these approaches within single imaging gene-environment interaction (IGxE) studies. We explore challenges inherent in both GxE and imaging genetics and highlight studies that address these limitations. In specifying IGxE models, we examine statistical methods for combining these approaches, and explore plausible biological mechanisms (e.g., epigenetics) through which these conditional mechanisms can be understood. Finally, we discuss the potential contribution that IGxE studies can make to understanding psychopathology and developing more personalized and effective prevention and treatment. PMID:21839667

Hyde, Luke W.; Bogdan, Ryan; Hariri, Ahmad R.

2011-01-01

421

Hybrid biosynthetic gene therapy vector development and dual engineering capacity  

PubMed Central

Genetic vaccines offer a treatment opportunity based upon successful gene delivery to specific immune cell modulators. Driving the process is the vector chosen for gene cargo packaging and subsequent delivery to antigen-presenting cells (APCs) capable of triggering an immune cascade. As such, the delivery process must successfully navigate a series of requirements and obstacles associated with the chosen vector and target cell. In this work, we present the development and assessment of a hybrid gene delivery vector containing biological and biomaterial components. Each component was chosen to design and engineer gene delivery separately in a complimentary and fundamentally distinct fashion. A bacterial (Escherichia coli) inner core and a biomaterial [poly(beta-amino ester)]-coated outer surface allowed the simultaneous application of molecular biology and polymer chemistry to address barriers associated with APC gene delivery, which include cellular uptake and internalization, phagosomal escape, and intracellular cargo concentration. The approach combined and synergized normally disparate vector properties and tools, resulting in increased in vitro gene delivery beyond individual vector components or commercially available transfection agents. Furthermore, the hybrid device demonstrated a strong, efficient, and safe in vivo humoral immune response compared with traditional forms of antigen delivery. In summary, the flexibility, diversity, and potential of the hybrid design were developed and featured in this work as a platform for multivariate engineering at the vector and cellular scales for new applications in gene delivery immunotherapy. PMID:25114239

Jones, Charles H.; Ravikrishnan, Anitha; Chen, Mingfu; Reddinger, Ryan; Kamal Ahmadi, Mahmoud; Rane, Snehal; Hakansson, Anders P.; Pfeifer, Blaine A.

2014-01-01

422

Practical Aspects of the Development of ex Vivoand in VivoGene Therapy for Parkinson's Disease  

Microsoft Academic Search

Current approaches to gene therapy of CNS disorders include grafting genetically modified autologous cells or introducing genetic material into cellsin situusing a variety of viral or synthetic vectors to produce and deliver therapeutic substances to specific sites within the brain. Here we discuss issues related to the application ofex-vivoandin-vivogene therapies as possible treatments for Parkinson's disease. Autologous monkey fibroblasts engineeredex-vivoto

Krzysztof S. Bankiewicz; Stuart E. Leff; Dea Nagy; Steve Jungles; Joseph Rokovich; Kaye Spratt; Lawrence Cohen; Michele Libonati; Richard O. Snyder; Ronald J. Mandel

1997-01-01

423

Imaging CXCL12-CXCR4 Signaling in Ovarian Cancer Therapy  

PubMed Central

Chemokine CXCL12 and receptor CXCR4 have emerged as promising therapeutic targets for ovarian cancer, a disease that continues to have a dismal prognosis. CXCL12-CXCR4 signaling drives proliferation, survival, and invasion of ovarian cancer cells, leading to tumor growth and metastasis. Pleiotropic effects of CXCR4 in multiple key steps in ovarian cancer suggest that blocking this pathway will improve outcomes for patients with this disease. To quantify CXCL12-CXCR4 signaling in cell-based assays and living mouse models of ovarian cancer, we developed a click beetle red luciferase complementation reporter that detects activation of CXCR4 based on recruitment of the cytosolic adapter protein ?-arrestin 2. Both in two-dimensional and three-dimensional cell cultures, we established that bioluminescence from this reporter measures CXCL12-dependent activation of CXCR4 and inhibition of this pathway with AMD3100, a clinically-approved small molecule that blocks CXCL12-CXCR4 binding. We used this imaging system to quantify CXCL12-CXCR4 signaling in a mouse model of metastatic ovarian cancer and showed that treatment with AMD3100 interrupted this pathway in vivo. Combination therapy with AMD3100 and cisplatin significantly decreased tumor burden in mice, although differences in overall survival were not significantly greater than treatment with either agent as monotherapy. These studies establish a molecular imaging reporter system for analyzing CXCL12-CXCR4 signaling in ovarian cancer, which can be used to investigate biology and therapeutic targeting of this pathway in cell-based assays and living mice. PMID:23372646

Salomonnson, Emma; Stacer, Amanda C.; Ehrlich, Anna; Luker, Kathryn E.; Luker, Gary D.

2013-01-01

424

Identification of Reduced-Order Thermal Therapy Models Using Thermal MR Images: Theory and Validation  

PubMed Central

In this paper, we develop and validate a method to identify computationally efficient site- and patient-specific models of ultrasound thermal therapies from MR thermal images. The models of the specific absorption rate of the transduced energy and the temperature response of the therapy target are identified in the reduced basis of proper orthogonal decomposition of thermal images, acquired in response to a mild thermal test excitation. The method permits dynamic reidentification of the treatment models during the therapy by recursively utilizing newly acquired images. Such adaptation is particularly important during high-temperature therapies, which are known to substantially and rapidly change tissue properties and blood perfusion. The developed theory was validated for the case of focused ultrasound heating of a tissue phantom. The experimental and computational results indicate that the developed approach produces accurate low-dimensional treatment models despite temporal and spatial noises in MR images and slow image acquisition rate. PMID:22531754

2013-01-01

425

Gene-based therapies for dominantly inherited retinopathies  

Microsoft Academic Search

In light of the elucidation of the molecular pathogenesis of some dominantly inherited retinal degenerations over the past two decades, it is timely to explore possible means of therapeutic intervention for such diseases. However, the presence of significant levels of intergenic and intragenic genetic heterogeneity in this group of dominant conditions represents a barrier to the development of therapies focused

G J Farrar; S Millington-Ward; N Chadderton; P Humphries; P F Kenna

2012-01-01

426

Differential targeting of feline photoreceptors by recombinant adeno-associated viral vectors: implications for preclinical gene therapy trials.  

PubMed

The cat is emerging as a promising large animal model for preclinical testing of retinal dystrophy therapies, for example, by gene therapy. However, there is a paucity of studies investigating viral vector gene transfer to the feline retina. We therefore sought to study the tropism of recombinant adeno-associated viral (rAAV) vectors for the feline outer retina. We delivered four rAAV serotypes: rAAV2/2, rAAV2/5, rAAV2/8 and rAAV2/9, each expressing green fluorescent protein (GFP) under the control of a cytomegalovirus promoter, to the subretinal space in cats and, for comparison, mice. Cats were monitored for gene expression by in vivo imaging and cellular tropism was determined using immunohistochemistry. In cats, rAAV2/2, rAAV2/8 and rAAV2/9 vectors induced faster and stronger GFP expression than rAAV2/5 and all vectors transduced the retinal pigment epithelium (RPE) and photoreceptors. Unlike in mice, cone photoreceptors in the cat retina were more efficiently transduced than rod photoreceptors. In mice, rAAV2/2 only transduced the RPE whereas the other vectors also transduced rods and cones. These results highlight species differences in cellular tropism of rAAV vectors in the outer retina. We conclude that rAAV serotypes are suitable for use for retinal gene therapy in feline models, particularly when cone photoreceptors are the target cell. PMID:25056608

Minella, A L; Mowat, F M; Willett, K L; Sledge, D; Bartoe, J T; Bennett, J; Petersen-Jones, S M

2014-10-01

427

Delivery of gene silencing agents for breast cancer therapy  

PubMed Central

The discovery of RNA interference has opened the door for the development of a new class of cancer therapeutics. Small inhibitory RNA oligos are being designed to specifically suppress expression of proteins that are traditionally considered nondruggable, and microRNAs are being evaluated to exert broad control of gene expression for inhibition of tumor growth. Since most naked molecules are not optimized for in vivo applications, the gene silencing agents need to be packaged into delivery vehicles in order to reach the target tissues as their destinations. Thus, the selection of the right delivery vehicles serves as a crucial step in the development of cancer therapeutics. The current review summarizes the status of gene silencing agents in breast cancer and recent development of candidate cancer drugs in clinical trials. Nanotechnology-based delivery vectors for the formulation and packaging of gene silencing agents are also described. PMID:23659575

2013-01-01

428

Should Gene Therapy be Used for Newborns with Hemophilia?  

E-print Network

of genetically-modified fibroblasts for he- mophilia A. The Food and Drug Administration has ruled out gene and initial evaluation in humans with other genetic deficiencies demonstrate safety and efficacy. The use

Ponder, Katherine P.