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

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of rejecting tumour cells from the patient, especially on immunoresponsive malignancies such as melanomas, colorectal carcinomas, and renal cell carcinomas Table 5. Ex vivo studies on animal models Boulikas: An overview on gene therapy Gene target Human disease ADA SCID (severe Retrovir Immunodeficiient mice were injected combined us with peripheral blood lymphocytes immunodeficie ncy) from ADA- patients transduced with a retroviral vector for human ADA bcl-2 prostate cancer bcl-2 expressing LNCaP human prostate cancer cells are rendered highly resistant to apoptotic stimuli Factor IX hemophilia B Injection of transduced primary myoblasts into the muscle 88 (Uchiyama et al, 1993; Chang et al, 1996; Finke et al, 1997; Das Gupta et al, 1997; Mahvi et al, 1997). Method Animal model, objective, and method Results Reference Factor IX hemophilia B retr Transplantation of retrovirustransduced keratinocytes Factor IX hemophilia B retroviru s Factor VIII Hemophilia A transferr in Factor VIII Hemophilia A Retrovir us Growth hormone (human) Growth hormone (human, hGH) none mice electrop oration Mouse primary myoblasts were infected with retrovirus expressing the canine factor IX under control of mouse muscle creatine kinase and human CMV promoter; myoblasts were injected into the hindlegs of recipient mice; secreted canine factor IX was monitored in the plasma Transfection of fibroblasts and myoblasts with B-domain-deleted factor VIII gene followed by implantation into mice Mouse primary fibroblasts infected with a recombinant retrovirus containing factor VIII gene deleted at the B domain Ex vivo modified C2C12 cells with the hGH gene under control of the inducible UAS promoter and a synthetic hybrid steroid receptor (TAXI), activating transcription from the inducible promoter after treatment with the synthetic nontoxic drug inducer RU486; transplanted in mouse muscle general retr Injection of genetically engineered myoblasts into mouse muscle HSV-tk glioma Retr To directly transfer HSV TK gene and kill transduced proliferating brain tumor cells with ganciclovir without affecting nondividing normal cells HSV-tk pancreatic cancer retroviru s BXPC3 primary human pancreatic adenocarcinoma cells were transduced with retroviral vector carrying the HSV-tk gene driven by the CEA promoter; engrafted subcutaneously into nude mice eliciting pancreatic tumors Restoration of immune functions (presence of human immunoglobulin and antigen-specific T cells) LNCaP-bcl-2 cells induced earlier, larger, and hormone-refractory prostate tumors in nude mice Factor IX was being synthesized and delivered to the circulation for over 6 months Human factor IX was detected in the bloodstream of nude mice in small quantities for one week Sustained expression of factor IX for over six months without any apparent adverse effects on the recipient mice; however, the levels of the factor IX protein secreted into the plasma (10 ng/ml for 107 injected cells) were not sufficient to be of therapeutic value; 100 times higher amounts of factor IX were needed Therapeutic levels of factor VIII in the blood of the animals for 24 hours Therapeutic levels of factor VIII in blood of animals for 1 week after surgical implantation into the peritoneal cavity in SCID mice of 15 million cells in the form of neoorgans This model allows up to 100-fold induction of the hGH gene and can be finely tuned to lower levels of induction hGH could be detected in serum for 3 months; myoblasts were fused into preexisting multinucleated myofibers that were vascularized and innervated Murine fibroblasts transduced ex vivo with HSV TK retroviral vectors caused complete regression of gliomas in rat brain after intratumor injection Animals treated with 0.1 mg/Kg ganciclovir exhibited a significant reduction in tumor growth Ferrari et al, 1991 Rafo et al, 1995 Dai et al, 1992 Gerrard et al, 1993, Dai et al, 1992; Yao et al, 1994 Zatloukal et al, 1994 Dwarki et al, 1995 Delort and Capecchi, 1996 Dhawan et al, 1991 Culver et al, 1992 DiMaio et al, 1994 HSV-tk proliferative retroviru Traction retinal detachment results Significant inhibition of PVR (killing Kimura et al, 1996
IL-1 - receptor antagonist protein gene IL-1 receptor antagonist (IL-1Ra) IL-2; GM- CSF LDL receptor Nerve Growth Factor (NGF) XPD (ERCC2) TH (Tyrosine hydroxylase) vitreoretinopat hy (PVR) Rheumatoid arthritis (RA) Rheumatoid arthritis (RA) stransduc ed rabbit dermal fibrobla sts Gene Therapy and Molecular Biology Vol 1, page 89 from proliferation of retinal pigment cells in the vitreous cavity of the eye; PVR may ensue after retinal surgery or trauma and can be induced in rabbit models by surgical vitrectomy. Retr Synovial cells were surgically removed from joints of animals with experimental arthritis, cultured, transduced with the IL-1 -receptor antagonist protein gene and reimplanted into the respective donors by intraarticular injection Retr Degradation of cartilage in RA is stimulated by IL-1; to inhibit IL-1; RA synovial fibroblasts transfected with the IL-1Ra gene were coimplanted with normal human cartilage in SCID mice prostate cancer Dunning rat R3327-MatLyLu prostate tumor model (an anplastic androgendependent, nonimmunogenic tumor that metastasizes to the lymph nodes and the lung); cytokine (IL-2)-secreting human tumor cell preparations (tumor vaccines) were used for the treatment of advanced human prostate cancer in rats Familial hypercholester olemia (FH) Alzheimer's disease xeroderma pigmentosum (XP) Parkinson's disease (PD) TH Parkinson disease (PD) TH Parkinson's disease (PD) TH Parkinson's disease (PD) Retr Watanabe heritable hyperlipidemic rabbit (deficient in both alleles of LDL receptor gene); establish hepatocyte culture from animal liver; transduce with LDL receptor gene responsible for LDL internalization into hepatocytes to reduce blood serum cholesterol; transplant hepatocytes into the animal rat and primate Delivery of NGF by ex vivo-modified allogeneic cells surrounded by a semipermeable membrane and implanted intrathecally Retr To transduce ex vivo human keratinocytes and produce skin grafts on immunodeficient mice; use it on XP patients as reconstructive surgery to alleviate cancers in UV-exposed areas Retrovir us Rat fibroblasts transduced with tyrosine hydroxylase (TH) produced and released L-dopa to the culture medium; Overexpress TH that converts tyrosine to L-DOPA to alleviate degeneration of dopaminergic nigrostriatal neurons (DNN) in PD rat models; unilateral destruction of DNN in animals with 6hydroxydopamine and administration of apomorphine caused PD rats to turn contralaterally (7 or more rotations/min). HSV Infection of 6-hydroxydopaminelesioned rats, used as a model of PD, with a defective herpes simplex virus type 1 vector expressing TH Lipofect in To alleviate the symptoms of PD in TH-deficient rats (PD animal models; perform colateral rotations at 15 rounds/min upon administration of apomorphine) 89 of proliferating cells in the retina) was observed in rabbit PVR models after injection into the vitreous cavity of rabbit dermal fibroblasts transduced in vitro; all eyes received 0.2 mg GCV on the following day and on day 4; Improvement in RA symptoms Bandara et al, 1993 IL-1Ra expression protected the cartilage from chondrocyte-mediated degradation. All animals with subcutaneously established tumors were cured; the cancer vaccine induced immunological memory that protected the animals from subsequent tumor challenge; GM- CSF was less effective than IL-2. 30-40% decrease in serum cholesterol that persisted for 4 months Release of NGF by the implant which is not subject to immunologic rejection due to the membrane The retroviral vector carrying the XPD gene and neoR under control of SV40 enhancer fully complemented the DNA repair deficiency of primary skin fibroblasts When grafted to the striatum of Fischer rats with a prior 6hydroxydopamine lesion, primary fibroblasts containing the TH transgene survived for 10 weeks, continued to express the transgene, and reduced rotational asymmetry. Implantation of transgenic immortalized fibroblasts and myoblasts intracerebrally improved rotational behavior Conversion of endogenous striatal cells into L-dopa-producing cells Primary muscle cells were transduced with TH cDNA under control of CMV promoter; 10 million cells were injected into brains of TH-deficient rats; this resulted in 75% decrease in Otani et al, 1996; Makarov et al, 1996; Muller-Ladner et al, 1997b Vieweg et al, 1994 Chowdhury et al, 1991 Kordower et al, 1994 Gözükara et al, 1994; Carreau et al, 1995 Wolff et al, 1989 Fischer et al, 1991 During et al, 1994 Jiao et al, 1993
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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
Page 37 and 38: 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
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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: transduced primary mouse fibroblast
Page 91 and 92: p53 lung cancer retroviru s MHC cla
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Page 97 and 98: Isolation of an RNA aptamer that ca
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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
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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
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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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