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Titolo:
Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus
Autore:
Harvey, BG; Leopold, PL; Hackett, NR; Grasso, TM; Williams, PM; Tucker, AL; Kaner, RJ; Ferris, B; Gonda, I; Sweeney, TD; Ramalingam, R; Kovesdi, I; Shak, S; Crystal, RG;
Indirizzi:
Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, Belfer Gene Therapy Core Facil, New York, NY 10021 USA Cornell Univ New York NY USA 10021 apy Core Facil, New York, NY 10021 USA Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, Div Pulm & Crit Care Med, New York, NY 10021 USA Cornell Univ New York NY USA 10021 Crit Care Med, New York, NY 10021 USA GenVec Inc, Rockville, MD 20852 USA GenVec Inc Rockville MD USA 20852GenVec Inc, Rockville, MD 20852 USA Genentech Inc, S San Francisco, CA 94080 USA Genentech Inc S San Francisco CA USA 94080 S San Francisco, CA 94080 USA
Titolo Testata:
JOURNAL OF CLINICAL INVESTIGATION
fascicolo: 9, volume: 104, anno: 1999,
pagine: 1245 - 1255
SICI:
0021-9738(199911)104:9<1245:AECMEI>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
TRANSMEMBRANE CONDUCTANCE REGULATOR; MEDIATED GENE-TRANSFER; MESSENGER-RNA TRANSCRIPTS; NASAL EPITHELIUM; TRANSGENE EXPRESSION; CHLORIDE TRANSPORT; RESPIRATORY-TRACT; CODING SEQUENCES; IMMUNE-RESPONSES; VECTOR;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
59
Recensione:
Indirizzi per estratti:
Indirizzo: Crystal, RG Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, Belfer Gene Therapy Core Facil, 520 E 70th St,ST 505, New York, NY 10021 USA Cornell Univ 520 E 70th St,ST 505 New York NY USA 10021 21 USA
Citazione:
B.G. Harvey et al., "Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus", J CLIN INV, 104(9), 1999, pp. 1245-1255

Abstract

We sought to evaluate the ability of an E1(-), E3(-) adenovirus (Ad) vector (Ad(GV)CFTR10) to transfer the normal human cystic fibrosis transmembraneconductance regulator (CFTR) cDNA to the airway epithelium of individuals with cystic fibrosis (CF). We administered Ad(GV)CFTR10 at doses of 3 x 10(6) to 2 x 10(9) plaque-forming units over 9 months by endobronchial spray to 7 pairs of individuals with CF. Each 3-month cycle, we measured vector-derived versus endogenous CFTR mRNA in airway epithelial cells prior to therapy, as well as 3 and 30 days after therapy. The data demonstrate that (a) this strategy appears to be safe; (b) after the first administration, vector-derived CFTR cDNA expression in the CF airway epithelium is dose-dependent, with greater than 5% endogenous CFTR mRNA levels at the higher vector doses; (c) expression is transient, lasting less than 30 days; (d) expression can be achieved with a second administration, but only at intermediate doses, and no expression is observed with the third administration; and (e) theprogressive lack of expression with repetitive administration does not closely correlate with induction of systemic anti-Ad neutralizing antibodies. The major advantage of an Ad vector is that it can deliver sufficient levels of CFTR cDNA to the airway epithelium so that CFTR expression protects the lungs from the respiratory manifestations of CF. However, this impressivelevel of expression is linked to the challenging fact that expression is limited in time. Although this can be initially overcome by repetitive administration, unknown mechanisms eventually limit this strategy, and further repetitive administration does not lead to repetitive expression.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/09/20 alle ore 01:58:04