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

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Boulikas: An overview on gene therapy Table 6. In vivo somatic gene transfer strategies to animal models Gene target or delivered HSV TK and ganciclovir Prostaglandi n G/H synthase Ornithine transcarbam ylase (OTC) α1antitrypsin α1antitrypsin α1antitrypsin (AT, human) Human disease hepatocellular carcinoma acute lung injury OTCdeficiency α1-antitrypsindeficiency in lung α1-antitrypsindeficiency in liver acute and chronic lung diseases. CFTR Cystic fibrosis (CF) CFTR (cystic fibrosis transmembra ne conductance regulator) Cystic fibrosis (CF) CFTR Cystic fibrosis (CF) 90 the number of rotations/min for more than 6 months Method Animal model, objective, and method Results Reference AAV mice Cat lipid rabbit Adenovi rus Adenovi rus Cat lipid mice To preferentially kill hepatocellular carcinoma cells by the suicadal gene HSV TK (driven by the α-fetal protein (AFP) enhancer and albumin promoter) with ganciclovir Rabbits intravenously transfected with the PGH synthase gene iv injection of recombinant adenovirus to spf-ash mice (OTC-deficient) The adenovirus major late promoter was linked to a human α1-antitrypsin gene for its transfer to lung epithelia of cotton rat respiratory pathway Protect connective tissue from the lytic action of the leukocyte neutrophil elastase; plasmid was encapsulated into negatively-charged liposomes containing phoshpatidylcholine Cat lipid Aerosol and intravenous transfection to lungs of rabbits Adenovi rus Selective killing of AFP-positive cells in culture; transgenic mice were established by injection of AAV ITRs, neoR , and HSV TK genes as a linear DNA fragment; HSV TK was expressed predominantly in adult liver. Increased plasma levels of prostacyclin and PGE2; protection of lungs in rabbits against endotoxininduced inflammation, pulmonary edema, release of thromboxane B2, and pulmonary hypertension Correction of enzyme deficiency in OTC-deficient mice for over 1 year. Both in vitro and in vivo infections have shown production and secretion of α1-antitrypsin by the lung cells for over 1 week Small liposomes were much more effective in delivering the α1antitrypsin gene to mouse hepatocytes in vivo. Human α1AT mRNA and protein were detected for at least 7 days; immunohistochemical staining showed α1AT protein in the pulmonary endothelium following intravenous administration, in alveolar epithelial cells following aerosol administration, and in the airway epithelium by either route To alleviate the symptoms of CF Expression of CFTR after intratracheal instillation into lungs of cotton rats; expression between days 2-10 Cat lipid To express the normal CFTR gene in lungs of Edinburgh insertional mutant mouse (cf/cf) after delivering CFTR cDNA-liposome complexes into the airways by nebulization. Lipofect in CFTR CF Lipofect in CFTR cDNA (human) Cystic fibrosis (CF) To express the human CFTR gene in lungs in CFTR-deficient transgenic mice by tracheal instillation of lipofectin-plasmid Transduction of airway epithelial cells in normal mice by intratracheal instillation of a plasmid carrying the CFTR gene under control of the Rous sarcoma virus promoter AAV Intratracheal instillation into neonatal New Zealand white rabbits Full restoration of cAMP related chloride responses in some animals; human CFTR cDNA expression in the same tissues Successful transfer of the CFTR gene to epithelia and to alveoli deep in the lung leading to correction of the ion conductance defects found in the trachea of transgenic mice Airway epithelial cells were the major target and site of expression of CFTR Epithelial expression of the human CFTR fusion protein was detected using antisera to both the human Su et al, 1996 Conary et al 1994 Stratford-Perricaudet et al, 1990 Rosenfeld et al, 1991 Aliño et al, 1996 Canonico et al, 1994 Rosenfeld et al, 1992 Alton et al, 1993 Hyde et al, 1993. Yoshimura et al, 1992 Rubenstein et al, 1997
p53 lung cancer retroviru s MHC class I HLA-B7 heavy chain gene plus β2microglobuli n CCK (cholecystok inin) congenital audiogenic epileptic seizures (AS) hirudin restenosis; arterial injury HSV-tk arterial injury; restenosis RB atherosclerosis, restenosis, arterial injury p21 atherosclerosis, restenosis, arterial injury Cat lipid:D NA 1:5 mice Lipofect in (DOTM A:DOP E) adenovir us Adenovi rus Adenovi rus Adenovi rus Gene Therapy and Molecular Biology Vol 1, page 91 Lung tumors were elicited in nu/nu mice after intratracheal inoculation with human lung cancer H226Br cells whose p53 gene has a homozygous mutation at codon 254 To give a complete Class I molecule with heavy and light chains; MHC class I HLA-B7 heavy chain gene has an internal ribosome entry site; the β2microglobulin was driven by RSV promoter To suppress audiogenic epileptic seizures by cholecystokinin octapeptide (CCK-8) injected intracerebroventricularly (i.c.v.) Virus-injured rat carotid arteries; hirudin (from medicinal leech) is a potent protein inhibitor of thrombin; thrombin converts fibrinogen to fibrin and also stimulates smooth muscle cell proliferation during neointima formation in the arterial walls To kill preferentially the smooth muscle cells and reduce neointima formation in the arterial wall To inhibit vascular smooth muscle cell (VSMC) proliferation after arterial injury To inhibit vascular smooth muscle cell (VSMC) proliferation after arterial injury; p21 protein functions both by inhibiting cyclin dependent kinases (CDKs) required for the initiation of S phase and by binding to and inhibiting PCNA ras arterial injury Transfer of ras transdominant negative mutants to rats in which the common carotid artery was subjected to balloon injury TGF-β arterial injury TGF-β accelerates wound healing and inhibits epithelial and smooth cell proliferation; loss of functional TGF-β receptors in cancer cells TGF-β1 Rheumatoid arthritis (RA) Gene target or delivered LDL receptor Very low density Human disease Familial hypercholester olemia (FH) Familial hypercholester 91 CFTR R domain and the aminoterminal epitope at up to 6 weeks after vector inoculation, a time coinciding with the completion of the alveolar phase of lagomorph lung development Intratracheal injection of a recombinant retrovirus containing the wt p53 gene was shown to inhibit the growth of the tumor Experiments in mice showed rapid (1 day) destruction of the plasmid in tissues; femtogram amounts only in muscle at 6 months postinjection AS in rats was markedly reduced between day 3 and 4. 35% reduction in neointima formation in hirudin cDNAtransduced arterial wall cells in vivo 47% reduction in I/M area ratio following local delivery of HSV-tk and systemic ganciclovir therapy Fujiwara et al, 1994 Lew et al, 1995 Zhang et al, 1992 Rade et al, 1996 Ohno et al, 1994; Guzman et al, 1994 42% reduction in I/M area ratio Chang et al, 1995a Over-expression of human p21 Chang et al, 1995b inhibited growth factor-stimulated VSMC proliferation and neointima formation in the rat carotid artery model of balloon angioplasty in vitro by arresting VSMCs in the G1 phase of the cell cycle Reduced neointimal formation Indolfi et al, 1995 Inhibition in epithelial and smooth cell proliferation Retr Mice with induced arthritis Effective in lowering inflammation of joints with already established arthritis and inhibiting the spreading of the disease to other joints in mice Grainger et al, 1995 Method Goal/rationale Results Reference Adeno Infusion of adenovirus human LDL-R cDNA into the portal vein of rabbits deficient in LDL receptor Human LDL receptor protein was produced in the majority of hepatocytes that exceeded the levels found in human liver by at least 10fold Adeno LDL-R knockout mice A single intravenous injection resulted in reduction in total Chernajovsky et al, 1997 Kozarsky et al, 1994 Kobayashi et al, 1996; Kozarsky et al, 1996
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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
Page 39 and 40: Gene Therapy and Molecular Biology
Page 41 and 42: C. Considerations of chromatin stru
Page 45 and 46: A. The molecular basis of cancer im
Page 47 and 48: fragments, or heat shock proteins c
Page 49 and 50: ecombinant vaccinia virus expressin
Page 51 and 52: HIV-1 envelope DNA construct develo
Page 53 and 54: inding sites A GYYY oriented in opp
Page 57 and 58: Prives, 1994). Whereas the wild-typ
Page 59 and 60: mutant p53 (mutations on p53 are wi
Page 61 and 62: master regulator of the cell cycle
Page 63 and 64: Work from several groups has shown
Page 65 and 66: chromatin condensation, drop in pH,
Page 67 and 68: Figure 23. A pathway leading to the
Page 69 and 70: Excessive necrotic death in cells o
Page 71 and 72: implantation, and similar processes
Page 73 and 74: normal cells in the surroundings. T
Page 79 and 80: A bicistronic retroviral vector (Ha
Page 81 and 82: C. Antisense ras gene transfer for
Page 83 and 84: equal to 6.0 showed S1 hyperreactiv
Page 85 and 86: protein (e.g. Smith et al, 1995; Fo
Page 87 and 88: transduced primary mouse fibroblast
Page 89: IL-1 - receptor antagonist protein
Page 95 and 96: designed by immunization with porti
Page 97 and 98: Isolation of an RNA aptamer that ca
Page 99 and 100: induction of human apoE in neonate
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Page 103 and 104: which eliminated tumors in small an
Page 105 and 106: C. Transfer of other genes against
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Page 111 and 112: (Prehn et al, 1996); this implies a
Page 113 and 114: B. Approaches to gene therapy of RA
Page 115 and 116: of human immunoglobulin and antigen
Page 117 and 118: A. Etiology and mechanisms of destr
Page 121 and 122: However, CsA also inhibits the acti
Page 123 and 124: The peptide kinin, after binding to
Page 125 and 126: intake when administered to adrenal
Page 127 and 128: Introgen Therapeutics (Austin and H
Page 129 and 130: When a subfragment of only 513 bp o
Page 131 and 132: Armentano D, Zabner J, Sacks C, Soo
Page 133 and 134: Brady HJM, Miles CG, Pennington DJ,
Page 135 and 136: Chen J, Stickles RJ, Daichendt KA (
Page 137 and 138: Day ML, Wu S, Basler JW (1993) Pros
Page 139 and 140: 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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