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Titolo:
Generation and characterization of E1/E2a/E3/E4-deficient adenoviral vectors encoding human factor VIII
Autore:
Andrews, JL; Kadan, MJ; Gorziglia, MI; Kaleko, M; Connelly, S;
Indirizzi:
Genet Therapy Inc, Gaithersburg, MD 20878 USA Genet Therapy Inc Gaithersburg MD USA 20878 c, Gaithersburg, MD 20878 USA
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 3, volume: 3, anno: 2001,
pagine: 329 - 336
SICI:
1525-0016(200103)3:3<329:GACOEA>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
PERSISTENT TRANSGENE EXPRESSION; P53 TUMOR-SUPPRESSOR; IN-VIVO EVALUATION; E4 GENE-PRODUCTS; HIGH-LEVEL; IMMUNE-RESPONSES; VIRAL-ANTIGENS; RECOMBINANT ADENOVIRUSES; SUSTAINED EXPRESSION; PHYSIOLOGICAL LEVELS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
59
Recensione:
Indirizzi per estratti:
Indirizzo: Connelly, S Genet Therapy Inc, 9 W Watkins Mill Rd, Gaithersburg, MD 20878USA Genet Therapy Inc 9 W Watkins Mill Rd Gaithersburg MD USA 20878
Citazione:
J.L. Andrews et al., "Generation and characterization of E1/E2a/E3/E4-deficient adenoviral vectors encoding human factor VIII", MOL THER, 3(3), 2001, pp. 329-336

Abstract

The use of adenoviral vectors for gene therapy has been limited due to host immune responses directed toward the vector and/or transgene and vector toxicity. To decrease adenoviral vector immunogenicity and toxicity, we attenuated viral gene expression by eliminating El, E2a, E3, and E4 early genesfrom the adenoviral backbone. Two highly attenuated, fourth-generation (Av4) E1/E2a/E3/E4-deficient adenoviral vectors encoding human factor VIII (FVIII) under the control of a liver-specific albumin promoter were generated. One Av4 vector (Av4 Delta E4FVIII) was deficient in the entire E4 coding region and the second vector contained a deletion of the E4 region, except for open reading frame 3 (orf 3; Av4orf3FVIII). The Av4 vectors were compared to an E1/E2a/E3-deficient third-generation vector (Av3H8101) containing an analogous transgene expression cassette in vitro and in vivo following intravenous administration in hemophiliac mice. In vitro transduction of Hep3B cells revealed at all three vectors expressed functional FVIII. However, the Av4 Delta E4FVIII vector could not be scaled-up for in vivo studies. Both Av3H8101 and Av4orf3FVIII initially expressed similar levels of FVIII inhemophiliac mice. However, at 3 months, animals treated with the Av4orf3FVIII vector no longer expressed FVIII while Av3H8101-treated mice displayed persistent FVIII expression. Liver enzyme analyses of plasma samples revealed that the Av4orf3FVIII vector was significantly less hepatotoxic than theAv3H8101 vector. These data demonstrate that further attenuation of the adenoviral vector backbone by removal of the majority of the E4 coding regionsignificantly diminished vector toxicity; however, the duration of transgene expression was reduced.

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Documento generato il 11/07/20 alle ore 17:16:15