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

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lipoprotein receptor (VLDL-R) HSV TK+ganciclo vir (GCV) HSV TK plus ganciclovir HSV TK plus ganciclovir Boulikas: An overview on gene therapy olemia (FH) cholesterol by approximately 50% at days 4 and 9; marked reduction in the intermediate density lipoprotein/low density lipoprotein (IDL/LDL) Gliomas Retr Treatment of rats with cerebral glioma; intratumoral stereotaxic injection of murine fibroblasts (G418-selected) producing a retroviral vector with the HSV TK gene prostate cancer Adenovi rus mouse adenocarcinom a TH PD Cat lipos rat rat glial cell line-derived neurotrophic factor (rGDNF), Ganciclovir is converted by HSV TK into its triphosphate form which is then incorporated into the DNA of replicating mammalian cells leading to inhibition in DNA replication and cell death; it is only viral TK, not the mammalian enzyme, that can use efficiently phosphorylated ganciclovir as a substrate Carcinoembryonic antigen-producing human lung cancer cells Overexpress TH to alleviate degeneration of dopaminergic nigrostriatal neurons (DNN) in PD rat models PD AAV To protect nigral dopaminergic neurons in the progressive Sauer and Oertel 6hydroxydopamine (6-OHDA) lesion model of Parkinson's disease (backlabeled fluorogold-positive neurons in the substantia nigra) Factor IX Hemophilia B Adenovi rus mice Factor IX Hemophilia B Adenovi rus mice in vivo Factor IX Hemophilia B Retrovir us dogs in vivo Factor IX Hemophilia B Adenovi rus dogs in vivo Correction of FIX defect by injection of recombinant adenovirus hosting the canine FIX gene into hind leg muscle of mice 92 Tretament with GCV 5 days postinjection resulted in complete regression of gliomas Subcutaneous tumors induced by injection of RM-1 (mouse prostate cancer) cells followed by injection of HSV TK and treatment with ganciclovir for 6 days showed reduction in tumor volume (16% of control) and higher apoptotic index in tumor cells Cell type-specific expression of herpes simplex virus thymidine kinase gene Direct injection of lipofectin-TH expression plasmid on nigra-lesioned side generated L-DOPA locally and decreased contralateral rotations. 94% cell protection; 85% of tyrosine hydroxylase-positive cells Establishment of factor IX levels in the blood in nude mice for 300 days; only for 10 days in normal mice; transduced cells were removed by cell-mediated as well as humoral immune responses; cyclophosphamide or cyclosporin A immunosuppression maintained FIX protein for 5 months Correction of the factor IX gene Therapeutic plasma levels of factor IX in mice Expression of factor IX gene in liver in hemophilia B dogs Establishment of the blood serum factor IX levels in hemophilic B dogs by infection with recombinant adenovirus vectors delivering the Factor IX gene and treatment with cyclosporin A 1% of hepatocytes were transduced with a retroviral vector carrying the canine factor IX gene injected into the portal vein (2/3 hepatectomy was required); low therapeutic levels of factor IX Treatment with cyclosporin A suppressed T cell activation; T cells attack the adenovirus-transduced cells eliminating them from the body; Cycl A tretment led to prolonged Factor IX levels in the blood of hemophilic dogs Factor IX Hemophilia B AAV Successful transduction of the mouse liver in vivo after a single administration; persistent, curative concentrations of functional human factor IX can be achieved Gene target or delivered Human disease Culver et al, 1992 Eastham et al, 1996 Osaki et al, 1994 Cao et al, 1995 Mandel et al, 1997 Dai et al, 1995 Smith et al, 1993 Kay et al, 1993 Kay et al, 1994; Fang et al, 1995 Snyder et al, 1997 Method Goal/rationale Results Reference
Gene Therapy and Molecular Biology Vol 1, page 93 Factor IX Hemophilia B AAV Intramuscular injection into hindlimb muscles of C57BL/6 mice and Rag 1 mice Factor X Hemophilia B Retr Delivery to rat hepatocytes in vivo during liver regeneration; under control of α1-antitrypsin promoter p53 breast carcinoma MDA-MB-435 cells Cdc2 kinase and PCNA vascular endothelial growth factor (VEGF) DOTM A:DOP E Restenosis liposom e-Sendai virus restenosis naked plasmid Kallikrein hypertension naked plasmid Nude mice inoculated with breast carcinoma cells (have mutated p53) Delivery to rat carotids after balloon injury; inhibition of Cdc2 kinase and PCNA with antisense oligonucleotides using PS:PC:Chol liposomes VEGF promotes endothelial cell proliferation to accelerate reendothelialization of the artery reducing intimal thickening Tissue kallikrein is a serine proteinase cleaving the kininogen to produce the vasoactive kinin peptide; kinin causes smooth muscle contraction and relaxation, increase in vascular permeability, and vasodilatation 93 Presence of hF.IX protein by immunofluorescence staining of muscles harvested 3 months after injection in both strains of mice; no plasma FIX in immunocompetent mice; Rag 1 mice which lack functional B and T cells, displayed therapeutic levels (200-350 ng/ml) of F. IX in the plasma in addition to F.IX in muscle cells 10% to 43% of normal human factor X levels in 4 rats; expression remained stable for more than 10 months in two rats Iv injection of p53 gene under control of β-actin promoter and intron every 10-12 days resulted in more than 60% reduction in tumor volume Whereas antisense cdc2 kinase or PCNA alone failed to have an effect, combination of the two antisense oligos significantly reduced neointima formation and smooth muscle cell proliferation after balloon injury VEGF gene expression using ELISA or RT-PCR was detected for 3-14 days after a single transfer using a hydrogel/polymer-coated ballon angioplasty catheter to induce simultaneous injury and delivery of plasmid to the femoral artery in rabbits. Significant reduction in blood pressure in spontaneously hypersensitive rats after a single delivery of naked DNA to portal vein which lasted for 5-6 weeks. Kallikrein hypertension Adeno Sustained delay in the increase in blood pressure from day 2 to day 41 post injection (iv) into spontaneously hypertensive rats; human tissue kallikrein mRNA was detected in the liver, kidney, spleen, adrenal gland, and aorta. Tissue kallikreinbinding protein (HKBP) or kallistatin Human endothelial NO synthase (eNOS) gene Antisense oligonucleoti des to AT1receptor mRNA and to angiotensino gen mRNA Endothelial basic FGF (bFGF) hypertension Adeno Kallistatin, a serine proteinase inhibitor, may function as a vasodilator in vivo hypertension Blood pressure is controled by the endothelium-derived nitric oxide (NO) in peripheral vessels hypertension Liposo mes Angiotensinogen, produces angiotensin I in the liver (component of the reninangiotensin system); mutations in the angiotensinogen (AT) gene are associated with hypertension hypertension Subphysiological amounts in blood vessels of spontaneously hypertensive rats Delivery of the human kallistatin cDNA/CMV by portal vein injection resulted in a significant reduction of blood pressure of hypertensive rats for 4 weeks. Significant reduction of systemic blood pressure for 5 to 6 weeks. Antisense oligonucleotides delivered to rat liver via the portal vein diminished the expression of hepatic angiotensinogen mRNA and reduced blood pressure. Restored the physiological levels levels of bFGF in the vascular wall and corrected hypertension Herzog et al, 1997 Le et al, 1997 Lesoon-Wood et al, 1995 Morishita et al, 1993 Isner et al, 1996 Chao et al, 1996 Jin et al, 1997 Chen et al, 1997 Lin et al, 1997 Tomita et al, 1995; Phillips, 1997; Phillips et al, 1997 Cuevas et al, 1996 Atrial hypertension Chronic infusion of ANP causes Significant reduction of systemic Lin et al, 1995
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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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Page 41 and 42: C. Considerations of chromatin stru
Page 43 and 44: Gene Therapy and Molecular Biology
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 and 90: IL-1 - receptor antagonist protein
Page 91: p53 lung cancer retroviru s MHC cla
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
Page 101 and 102: atrium in heart, endothelial cells
Page 103 and 104: which eliminated tumors in small an
Page 105 and 106: C. Transfer of other genes against
Page 109 and 110: significant reduction in neointima
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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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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