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

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A clinical protocol proposed recently for the therapy of amyotrophic lateral sclerosis uses a semipermeable membrane to enclose the ex vivo modified xenogenic BKH cells which is implanted intrathecally to provide human ciliary neurotrophic factor; the membrane prevents immunologic rejection of the cells interposing a virus impermeable barrier between the transduced cells and the host (Deglon et al, 1996; Pochon et al, 1996); the method has been applied before for cross-species transplantation of a polymer-encapsulated dopamine-secreting cell line to treat Parkinson's disease and for the delivery of nerve growth factor in rat and primate models of the Alzheimer's disease (Kordower et al, 1994; see Pochon et al, 1996 for more references). Evidently, similar approaches could be used to protect adenovirus- and retrovirus-transduced syngeneic cells from immunologic rejection provided that the therapeutic protein is secreted. A new area of investigation is directed toward surface modification of recombinant adenoviruses to render them safer and to minimize the strong immune responses against the virus and virus-infected cells; to this end Fender et al (1997) proposed a dodecahedron made of adenovirus pentons or penton bases and having only one or two adenovirus proteins instead of the 11 contained in an adenovirus virion; the penton is a complex of two oligomeric proteins, a penton base and fiber, involved in Figure 2. Localization of a recombinant adenoviral vector carrying 6.3 kb of dystrophin cDNA by in situ PCR following intramuscular injection to immunosuppressed mdx mice. Shown are transverse cryostat sections of mdx tibialis anterior muscle. Panel A shows a strong in situ hybridization signal (an E4 adenoviral sequence was amplified and an E4 probe was used) in myonuclei of an immunosuppressed animal injected with E1, E3-deleted adenovirus at 30 days postinjection (magnification 650x). Panel B was produced without Taq polymerase during PCR as a negative control. Panel C shows an uninjected muscle Boulikas: An overview on gene therapy 12 the cell attachment, internalization, and liberation of virus from endosomes. It is certain that great improvements in adenoviral gene delivery will solve many of the current problems and permit a higher therapeutic efficacy in the near future. G. Examples of adenoviral gene transfer Recombinant adenovirus vectors have been used: for the transfer of factor IX gene in hemophilia B dogs via vein injection (Kay et al, 1994) and in mice (Smith et al, 1993); for the transfer of genes into neurons and glia in the brain (le Gal la Salle, 1993); for the transfer of the gene of ornithine transcarmylase in deficient mouse and human hepatocytes (Morsy et al, 1993); for the transfer of the VLDL receptor gene for treatment of familial hypercholesterolaemia in the mouse model (Kozarsky et al, 1996); for the transfer of low density lipoprotein receptor gene in normal mice (Herz and Gerard, 1993); and for the ex vivo transduction of T cells from ADAdeficient patients (Blaese et al, 1995; Bordignon et al, 1995). The adenovirus major late promoter was linked to a human α1-antitrypsin gene for its transfer to lung epithelia of cotton rat respiratory pathway as a model for the treatment of α1-antitrypsin deficiency; both in vitro and in vivo infections
processed as described in panel A showing no hybridization signal. From Zhao JE, Lochumuller H, Nalbantoglu J, Allen C, Prescott S, Massie B, Karpati G (1997) Study of adenovirus-mediated dystrophin minigene transfer to skeletal muscle by combined microscopic display of adenoviral DNA and dystrophin. Hum Gene Ther 8, 1565- 1573. With kind permission of the authors (George Karpati, Montreal Neurological Institute, Canada) and Mary Ann Liebert, Inc. have shown production and secretion of α1-antitrypsin by the lung cells (Rosenfeld et al, 1991). A transductional preference of adenovirus-polylysine- DNA complexes and E1A/B-deleted replication-deficient adenoviruses was demonstrated for the prostate carcinoma cell lines DU145, LNCaP, and PC-3 over primary human bone marrow cells and the leukemia cell line KG-1; this finding led to a strategy to purge bone marrow of a specific subset of prostate carcinoma cells (Kim et al, 1997). Figure 2 shows the localization of a recombinant adenoviral vector carrying 6.3 kb of dystrophin cDNA, driven by the CMV promoter, by in situ PCR following intramuscular injection to immunosuppressed mdx mice. Figure 3. shows a comparison of the persistence of dystrophin expression and adenoviral genomes in immunosuppressed versus immunocompetent mdx mice. The maximum number of fibers containing recombinant adenovirus was maintained until 60 days in Gene Therapy and Molecular Biology Vol 1, page 13 13 immunosuppressed mice but for only 10 days in immunocompetent animals. Thus, optimization of immunosuppression could assure successful long term dystrophin gene transfer for gene therapy of Duchenne muscular dystrophy (Zhao et al, 1997). A number of RAC-approved protocols for gene transfer to humans use recombinant adenoviruses (Appendix 1, protocols 118-157). Genes transferred to patients with recombinant adenoviruses include p53 (#130, 131, 147, 148, 152-156), RB (#140), CFTR (#118- 123, 125, 128, 129), HSV-tk (126, 127, 132, 136, 139, 141, 143, 145, 146), cytosine deaminase (#134, 151), VEGF (#157), IL-2 (#135), GM-CSF (#149, 150), antierbB-2 single chain antibody (#133), ornithine transcarbamylase (#137), and GP100 melanoma antigen (#142).
Page 1 and 2: Gene Ther Mol Biol Vol 1, 1-172. Ma
Page 3 and 4: I. Introduction Monumental progress
Page 5 and 6: The use of retroviral vectors in hu
Page 7 and 8: displaying the cleavable EGF domain
Page 9 and 10: molecules in the nucleus (Lowe and
Page 11: sensitive mutations which allow pro
Page 15 and 16: On the contrary, the payload capaci
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Page 25 and 26: delivered by Sendai virus-liposome
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Page 33 and 34: B. Transcription factor binding sit
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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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Gene Therapy and Molecular Biology
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A bicistronic retroviral vector (Ha
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C. Antisense ras gene transfer for
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equal to 6.0 showed S1 hyperreactiv
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protein (e.g. Smith et al, 1995; Fo
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transduced primary mouse fibroblast
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IL-1 - receptor antagonist protein
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p53 lung cancer retroviru s MHC cla
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designed by immunization with porti
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Isolation of an RNA aptamer that ca
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induction of human apoE in neonate
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atrium in heart, endothelial cells
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which eliminated tumors in small an
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C. Transfer of other genes against
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significant reduction in neointima
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(Prehn et al, 1996); this implies a
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B. Approaches to gene therapy of RA
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of human immunoglobulin and antigen
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A. Etiology and mechanisms of destr
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However, CsA also inhibits the acti
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The peptide kinin, after binding to
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intake when administered to adrenal
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Introgen Therapeutics (Austin and H
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When a subfragment of only 513 bp o
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Armentano D, Zabner J, Sacks C, Soo
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Brady HJM, Miles CG, Pennington DJ,
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Chen J, Stickles RJ, Daichendt KA (
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Day ML, Wu S, Basler JW (1993) Pros
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Farmer G, Bargonetti J, Zhu H, Frie
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Giovannangeli C, Perrouault L, Escu
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the neoplastic phenotype by replace
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integrate in a site-specific fashio
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Li R, Waga S, Hannon GJ, Beach D, S
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adiation-induced apoptosis in the g
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Nakaya T, Iwai S, Fujinaga K, Sato
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Polyak K, Xia Y, Zweier JL, Kinzler
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macrophages from simian immunodefic
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intimal hyperplasia in a rat caroti
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Trono D, Feinberg MB, Baltimore D (
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Wattiaux R, Jadot M, Warnier-Pirott
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similar to mammalian interleukin-1
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24. Gene Marking /Infectious Diseas
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Drug 50. Gene Therapy /Phase I /Can
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76. Gene Therapy /Phase I /Cancer /
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99. Gene Therapy /Phase II /Cancer
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120. Gene Therapy /Phase I /Monogen
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cancer not specified) /Immunotherap
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