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

More documents

Recommendations

Info

a modified tTA transactivator gene engineered with the ligand-binding domain of the estrogen receptor to the carboxy terminus of the tTA transactivator; a single retroviral vector could transduce both the transactivator gene and the VSV-G protein gene controlled by the tTAinducible promoter into mammalian cells (Iida et al, 1996). The tetracycline-inducible system was modified by fusing the ligand binding domain of the estrogen receptor to the carboxy terminus of a tetracycline-regulated transactivator to regulate VSV-G expression in a tetracycline-dependent manner that could be modulated by β-estradiol in stable packaging cell lines (Chen et al, 1996). D. Limitations and advancements using retroviral vectors Before the in vivo gene therapy with retroviruses becomes a successful reality a number of problems must be overcome. Despite the extensive use of retroviral vectors in gene therapy, there are still problems to be solved and there is an ultimate need for the development of new, improved retroviral vectors and packaging systems to fuel further advances in the field of human gene therapy. The principle limitation of retroviruses has been poor gene expression in vivo which has been overcome through the use of tissue-specific promoters. Use of internal ribosome entry sites from picornaviruses in retroviral vectors has provided stable expression of multiple gene enhancers (reviewed by Naviaux and Verma, 1992; Boris-Lawrie and Temin, 1993). Little is known about the factors that influence the efficiency of retroviral infection in vivo. Many commonly used experimental animal strains, such as mice, harbor endogenous C-type proviruses, some of which are expressed and have circulating antibodies against the viral envelope glycoproteins that cross-react with the Mo-MLV; the efficiency of retrovirus-mediated transfection in vivo using a variety of mouse strains was affected by humoral immune competence and interference between endogenous MLVs and exogenous recombinant Mo-MLV (Fassati et al, 1995). One of the drawbacks of retroviruses for their exploitation in gene therapy has been the low viral titers obtained, too low to achieve therapeutic levels of gene expression; methods for the efficient concentration from large volumes of supernatant and purification of amphotropic retrovirus particles have been developed in several laboratories. For example, Bowles et al (1996) have used concentration and further purification of virus particles by sucrose banding ultracentrifugation; animal studies have shown that viral transduction increased proportionally with titer of the retrovirus. Transduced cells producing retrovirus are tissueincompatible and are, therefore, expected to be attacked by Boulikas: An overview on gene therapy 6 the immune system; this will lead to the elimination of therapeutic cells from the body, a phenomenon markedly associated also with adenoviral gene transfer. A privileged exception are brain tumor cells expressing recombinant retrovirus which persist without immunologic rejection (Culver et al, 1992). Sodium butyrate treatment of murine retrovirus packaging cells producing a CFTR vector increased the production of the retrovirus vector between 40- and 1,000fold (Olsen and Sechelski, 1995). The Cre/LoxP recombinase strategy (see below) has been used to generate retroviral vectors that have the ability to excise themselves after inserting a gene into the genome, thereby avoiding problems encountered with conventional retrovirus vectors, such as recombination with helper viruses or transcriptional repression of transduced genes (Russ et al, 1996). Retroviral vectors with the Cre/LoxP technology have also been used to deliver the GM-CSF gene to K562 cell culture (Fernex et al, 1997), for the development of retroviral suicide vectors for gene therapy using the HSV-tk gene (Bergemann et al, 1995), and for the production of a high-titer producer cell line containing a single LoxP site flanked by the viral LTRs (Vanin et al, 1997). Because retrovirus vectors are integrated into the genome, transcriptional repression of transduced genes will often take place from position effects exerted from neighboring chromatin domains; two matrix-attached regions (MARs), one at either flank of the transgene, are proposed here to insulating the gene in the retrovirus vector from chromatin effects at the integration site by creating an independent realm of chromatin structure harboring the transgene. MAR insulators have been used and can enhance up to 2,000-fold the expression of genes in transgenic animals and plants (McKnight et al, 1992; Breyne et al, 1992; Allen et al, 1993; Brooks et al, 1994; Thompson et al, 1994; Forrester et al, 1994). E. Targeting of retrovirus to specific cell types A number of approaches have been directed to develop retroviral vectors that are able to target particular cell types; also efforts focus toward retroviral vectors that incorporate nonretroviral features and are tailored to desired needs for specific uses (reviewed by Vile and Russell, 1995; Gunzburg and Salmons, 1996). Ideally, therapeutic genes should be delivered only to the relevant cell type and/or expressed in this cell type. Viral and nonviral vectors can be targeted through ligandreceptor interactions. Retroviral targeting through protease-substrate interactions has also been described; epidermal growth factor (EGF) was fused to a retroviral envelope glycoprotein via a cleavable linker comprising a factor Xa protease recognition signal. Vector particles
displaying the cleavable EGF domain could bind to EGF receptors on human cells but did not transfer their genes until they were cleaved by factor Xa protease (Nilson et al, 1996). A retroviral vector that infects human cells specifically through recognition of the low density lipoprotein receptor has been described by adding onto the ecotropic envelope protein of M-MLV a single-chain variable fragment derived from a monoclonal antibody recognizing the human LDL-R; the chimeric envelope protein was used to construct a packaging cell line producing a retroviral vector capable of transfer of the lacZ gene to human cells expressing LDL-R (Somia et al, 1995). F. Other retroviruses Viruses that contain RNA as their genetic material may be either negative- or positive-strand RNA viruses. The very large group of negative-strand RNA viruses includes some of the most serious and notorious pathogens subdivided into those with segmented RNA (influenza viruses, comprising eight separate segments of RNA and bunyaviruses containing three segments of single-stranded RNA, the large, L, the medium, M, and the small, S) and those with nonsegmented RNA (VSV, rabies, measles, Sendai, respiratory syncytial virus, Ebola viruses). Positive-strand RNA viruses include poliovirus. Cloned positive-strand poliovirus cDNA is infectious but neither isolated genome nor antigenome RNA of negative-strand viruses is infectious; this is because the negative-strand viral RNA is assembled with viral nucleoprotein into an RNP complex that becomes the template for the viral RNA-dependent RNA polymerase. Helper influenza virus-dependent procedures have been developed in which an influenza virus-like RNA molecule, containing a reporter gene, was mixed with disrupted virion core proteins to reconstitute RNP complexes in vitro which were then transfected into influenza virustransfected cells. Recombinant nucleocapsid and polymerase proteins for the unsegmented RNA viruses have also been used to produce infectious virus without help from an homologous virus using full-length cDNA clones of intracellularly transcribed antigenomes (rabies, VSV, measles, Sendai) (see Bridgen and Elliott, 1996 and the references cited therein). Plasmids containing full-length cDNA copies of the three RNA genome molecules of Bunyamwera bunyavirus and a negative-sense copy of the GFP gene, flanked by T7 promoter and hepatitis delta virus ribozyme sequences, were used to produce infectious virus particles without helper virus; these plasmids were used to transfect HeLa cells which expressed T7 RNA polymerase and recombinant Bunyamwera bunyavirus proteins by previous transfection with the appropriate plasmids; 24 h after infection about 1 in 1,000 HeLa cells displayed Gene Therapy and Molecular Biology Vol 1, page 7 7 fluorescence indicative of transcription and replication of the reporter RNA (Bridgen and Elliott, 1996). III. Adenoviral gene delivery A. Adenovirus replication, transcription, and attachment to the nuclear matrix Before understanding the principle of adenoviral gene transfer, it is essential to comprehend the molecular events which are involved in the life cycle of the adenovirus. Adenoviruses posses a well-defined origin of replication which is stimulated by transcription factors NFI and NFIII (Hay, 1985; Pruijn et al, 1986). The transcription factor NF-I (also called CTF, CCAAT box-binding protein, or C/EBP) stimulates replication of adenovirus DNA in vitro (Pruijn et al, 1986; Jones et al, 1987; Santoro et al, 1988; Coenjaerts et al, 1991) by establishing cooperative interactions with Ad-DBP (Adenovirus DNA-binding protein) (Cleat and Hay, 1989). The transcription factor NFIII (also called Oct-1 or OTF-1), involved in the regulation of the histone H2B and immunoglobulin genes, can stimulate initiation of adenovirus DNA replication in vitro (O'Neil et al., 1988; Mul et al, 1990; Verrijzer et al, 1990; Coenjaerts et al, 1991). The adenovirus 5 protein Ad-DBP is a single-stranded DNA binding protein product of the viral E2A absolutely required for chain elongation during Ad5 DNA replication; other than facilitating unwinding of the DNA, Ad-DBP might also protect single-stranded DNA at the replication fork from nuclease attack, increase the rate of processivity of the viral DNA polymerase, and increase binding of NFI of the core origin of Ad5 (Cleat and Hay 1989). This protein has a size of 529 amino acids, is phosphorylated and apart from its role in DNA replication is also involved in transcription, recombination, transformation, and virus assembly (see Tucker et al 1994). Crystal structure at 2.6 A resolution of Ad-DBP shows that a 17 aa C-terminal domain hooks onto a second Ad-DBP molecule thus promoting its cooperativity during DNA binding; Ad DBP was proposed to act by forming a core around which single-stranded DNA winds (Tucker et al, 1994). Adenoviruses replicate episomally; they need to attach to the nuclear matrix of the host cell for their replication. Two adenoviral proteins have been found attached to the nuclear matrix and presumably mediating the anchorage of the adenovirus: (i) the E1a protein (11 kDa), a transcription and replication factor sufficient to immortalize primary rodent cells, which was crosslinked to matrix proteins with oxidation with ophenanthroline/Cu 2+ (Chatterjee and Flint, 1986) and (ii) the adenovirus terminal protein (55 kDa) which is covalently attached to the 5' end of Ad DNA and initiates DNA replication; the adenovirus terminal protein mediated adenovirus anchorage to nuclear matrix was
Page 1 and 2: Gene Ther Mol Biol Vol 1, 1-172. Ma
Page 3 and 4: I. Introduction Monumental progress
Page 5: The use of retroviral vectors in hu
Page 9 and 10: molecules in the nucleus (Lowe and
Page 11 and 12: sensitive mutations which allow pro
Page 13 and 14: processed as described in panel A s
Page 15 and 16: On the contrary, the payload capaci
Page 17 and 18: in K562 human erythroleukemia cells
Page 19 and 20: defective HSV virus (DeLuca and Sch
Page 21 and 22: complex into the cytosol from the e
Page 23 and 24: Gene Therapy and Molecular Biology
Page 25 and 26: delivered by Sendai virus-liposome
Page 27 and 28: plasmids with the cell surface, tra
Page 29 and 30: infected by adenovirus alone; infec
Page 33 and 34: B. Transcription factor binding sit
Page 35 and 36: A closely related family of ubiquit
Page 37 and 38: cells. I-CreI is a member of this c
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 75 and 76:
Gene Therapy and Molecular Biology
Page 77 and 78:
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 and 92:
p53 lung cancer retroviru s MHC cla
Page 93 and 94:
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 107 and 108:
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 119 and 120:
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
Page 141 and 142:
Giovannangeli C, Perrouault L, Escu
Page 143 and 144:
the neoplastic phenotype by replace
Page 145 and 146:
integrate in a site-specific fashio
Page 147 and 148:
Li R, Waga S, Hannon GJ, Beach D, S
Page 149 and 150:
adiation-induced apoptosis in the g
Page 151 and 152:
Nakaya T, Iwai S, Fujinaga K, Sato
Page 153 and 154:
Polyak K, Xia Y, Zweier JL, Kinzler
Page 155 and 156:
macrophages from simian immunodefic
Page 157 and 158:
intimal hyperplasia in a rat caroti
Page 159 and 160:
Trono D, Feinberg MB, Baltimore D (
Page 161 and 162:
Wattiaux R, Jadot M, Warnier-Pirott
Page 163 and 164:
similar to mammalian interleukin-1
Page 165 and 166:
Page 167 and 168:
24. Gene Marking /Infectious Diseas
Page 169 and 170:
Drug 50. Gene Therapy /Phase I /Can
Page 171 and 172:
76. Gene Therapy /Phase I /Cancer /
Page 173 and 174:
99. Gene Therapy /Phase II /Cancer
Page 175 and 176:
120. Gene Therapy /Phase I /Monogen
Page 177 and 178:
Page 179 and 180:
cancer not specified) /Immunotherap
show all

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

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?