01. Gene therapy Boulikas.pdf - Gene therapy & Molecular Biology

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This field is in its infancy; however, animal studies showed that treatment of obese persons is one of the future prospects of gene therapy. Adenovirus-mediated transfer of the mouse leptin cDNA in the ob/ob mouse (which is genetically deficient in leptin and exhibits both an obese and a mild non-insulin-dependent diabetic phenotype) resulted in dramatic reductions in both food intake and body weight, as well as the normalization of serum insulin levels and glucose tolerance (Muzzin et al, 1996). Thus, transfer of the leptin gene can correct the obese and diabetic phenotypes in the adult ob/ob mice; these studies also provided confirming evidence that the control in body weight may be critical in the long-term management of non-insulin-dependent diabetes mellitus in obese patients. Infusion of a recombinant adenovirus containing the rat leptin cDNA under control of the CMV promoter to Wistar rats (8 ng/ml for 28 days) made them hyperleptinemic; these animals exhibited a 30-50% reduction in food intake and gained only 22 g over the experimental period versus 115-132 gained by control animals. Body fat was absent and plasma triglycerides and insulin levels were significantly lower in hyperleptinemic compared to control rats (Chen et al, 1996). On the contrary, delivery of the rat neuropeptide Y (NPY) cDNA with AAV and Sendai virosomes into the rat hypothalamic para-ventricular nucleus increased body weight and food intake for 21 days (Wu et al, 1996). XLII. Profile of Biotech companies: the big race Boulikas: An overview on gene therapy 126 Research and drug development in Biotech Industry have played and continue to play an important role in advancing molecular medicine. A number of Biotechnology Companies sponsor ongoing gene therapy Clinical Trials led by Genetic Therapy Incorporated (part of Novartis, Gaithersburg, MD) with the phase III trial in glioblastoma. Biotech Companies have the expertise and resources in large scale production, regulatory affairs, and clinical development to take off the basic science of gene therapy into the skies of commercialization and clinical trials. This is more evident in USA where strong bridges between the academia and industry have been established and numerous biotechnology companies dedicated to gene therapy have been founded. As of 1997 Europe lags some 3 to 5 years behind USA in translating basic science into commercial technology; however, European Pharmaceutical Companies have invested $1.4 billion in the American gene and cell therapy industry (compared with a modest $140 million investment from USA biotech firms to European partners). It is certain that both USA and Europe will ultimately benefit from the successful gene therapy development (Martin, 1997). Table 8 gives a glimpse of the role of Biotech Industry in drug discovery related to gene therapy and the clinical trials sponsored. Table 8. Biotech companies and drug development related to genes or cancer targeting Company Drug/Gene type Goal/Disease Status of drug development (end of 1997) Calydon (San Francisco, CA) Prostate cancer gene therapy Preclinical trials Canji/Schering-Plough (San Diego, CA) Canji/Schering-Plough (San Diego, CA) p53 to restore p53-mediated tumor suppression or apoptosis RB to restore RB-mediated cell cycle arrest Colon with hepatic metastases(#131); prostate (#148) Bladder(#140), non-small cell lung cancer (#156), lung, ovarian, and liver cancers Phase I Early clinical trials Cell Genesys, Inc CC49-Zeta T cell receptor Colorectal carcinomas expressing the tumorassociated antigen, TAG-72 (#110) Phase I /II Cell Genesys, Inc CD4-zeta Chimeric Receptor HIV (#85, 116) Phase I-II Chiron Corporation (Emerville HIV-1IIIB envelope protein HIV Phase I & San Diego CA) (#108) IDUN Pharmaceutical (San Diego, CA) bcl-2 inhibition Preclinical trials Incyte Pharmaceuticals (Palo Alto, CA) Gene sequence databases License access to database for drug discovery to different companies
Introgen Therapeutics (Austin and Houston, TX) Gene Therapy and Molecular Biology Vol 1, page 127 p53 gene therapies to restore p53-mediated tumor suppression or apoptosis α1-Antitrypsin cDNA/cationic lipids 127 Lung, head and neck cancers, prostate cancer (#154) Phase I-II Gene Medicine, Inc. (The Woodlands, Texas) α1-antitrypsin deficiency (#194) Phase I Gene Medicine, Inc. Human insulin-like growth Cubital Tunnel syndrome Phase I factor-1(hIGF-1) (#164) Genetic Therapy, Inc. /Novartis HSV-tk brain tumors (#17), recurrent Phase I (Gaithersburg, MD) pediatric brain tumors (#45), recurrent glioblastoma (#32, 97, 99), astrocytoma (#42, 68), leptomeningeal carcinomatosis (#49), multiple myeloma (#75) Genetic Therapy, Inc. /Novartis CFTR/adenovirus vector Cystic fibrosis (#121) Phase I Genetic Therapy, Inc. /Novartis Glucocerebrosidase cDNA Gaucher disease (#39) Phase I Genset Isolation of regulatory regions Genta (La Jolla, CA) bcl-2 inhibition with antisense cancer Early clinical trials Genzyme Corporation CFTR/adenovirus Cystic fibrosis (#120, 128, 129, Phase I (Framingham, MA) vector/cationic lipids 203) GenVec, Inc. VEGF121 cDNA to the ischemic myocardium Coronary artery disease (#157) Phase I Glaxo Wellcome Inc. CFTR/Cationic Liposome Complex Cystic fibrosis Phase I LXR (Richmond, CA) Antiapoptotics Advanced clinical trials Mitotix (Cambridge, MA) Cell cycle inhibitors Preclinical trials Myriad Genetics (Salt Lake Diagnostic genetic testing BRAC analysis kit for breast In the market City, UT) cancer Onyx (Richmond, CA) p53 gene therapies killing cells that lack p53 Early clinical trials Ribozyme Pharmaceuticals, Inc Tat and Rev Hammerhead HIV replication inhibition Phase II (Boulder, CO) Ribozyme (#117) Ribozyme Pharmaceuticals, Inc (Boulder, CO) Growth factor inhibition Preclinical trials Rhône-Poulenc Rorer Gencell p53 Head and neck squamous cell Phase II (Vitry-sur-Seine, France & Santa Clara, California) carcinoma (#152) SEQUUS Pharmaceuticals Doxorubicin encapsulated into Kaposis sarcoma In the market (Doxil); clinical (Menlo Park, CA) “stealth” liposomes trials for other cancers SUGEN (Redwood City, CA) Tyrosine kinase inhibitor to inhibit PDGF receptor Gliomas Clinical trials Targeted Genetics Corporation HSV-tk HIV (#81) Phase I/II Targeted Genetics Corporation E1A/ DC-Chol-DOPE Metastatic breast or ovarian cancer, metastatic solid tumors that overexpress HER-2 /neu Phase I Targeted Genetics Corporation CFTR/AAV Cystic fibrosis Phase I Vical, Inc. Tumor idiotype Non-Hodgkin’s B-cell lymphoma (#161) Phase I/II Vical, Inc. (San Diego, β-2 Microglobulin Immunotherapy of advanced Phase I/II California) cDNA/cationic lipids colorectal carcinoma, renal cancer (#195), melanoma (#196), metastatic malignancies (#201) Vical, Inc. Interleukin-2 cDNA Lymphoma (#198), solid tumor immunotherapy (#211) Phase I Vical, Inc. HLA B7 cDNA Renal cancer immunotherapy Phase I
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Gene Ther Mol Biol Vol 1, 1-172. Ma
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I. Introduction Monumental progress
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The use of retroviral vectors in hu
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displaying the cleavable EGF domain
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molecules in the nucleus (Lowe and
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sensitive mutations which allow pro
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processed as described in panel A s
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On the contrary, the payload capaci
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in K562 human erythroleukemia cells
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defective HSV virus (DeLuca and Sch
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complex into the cytosol from the e
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Gene Therapy and Molecular Biology
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delivered by Sendai virus-liposome
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plasmids with the cell surface, tra
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infected by adenovirus alone; infec
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B. Transcription factor binding sit
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A closely related family of ubiquit
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cells. I-CreI is a member of this c
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C. Considerations of chromatin stru
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A. The molecular basis of cancer im
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fragments, or heat shock proteins c
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ecombinant vaccinia virus expressin
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HIV-1 envelope DNA construct develo
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inding sites A GYYY oriented in opp
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Prives, 1994). Whereas the wild-typ
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mutant p53 (mutations on p53 are wi
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master regulator of the cell cycle
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Work from several groups has shown
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chromatin condensation, drop in pH,
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Figure 23. A pathway leading to the
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Excessive necrotic death in cells o
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implantation, and similar processes
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normal cells in the surroundings. T
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Page 79 and 80: A bicistronic retroviral vector (Ha
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cancer not specified) /Immunotherap
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