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Titolo:
Acute direct adenoviral vector cytotoxicity and chronic, but not acute, inflammatory responses correlate with decreased vector-mediated transgene expression in the brain
Autore:
Thomas, CE; Birkett, D; Anozie, I; Castro, MG; Lowenstein, PR;
Indirizzi:
Univ Manchester, Sch Med, Mol Med & Gene Therapy Unit, Manchester M13 9PT,Lancs, England Univ Manchester Manchester Lancs England M13 9PT r M13 9PT,Lancs, England
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 1, volume: 3, anno: 2001,
pagine: 36 - 46
SICI:
1525-0016(200101)3:1<36:ADAVCA>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
WILD-TYPE; INFECTION; DELIVERY; PROMOTER; NUCLEUS;
Keywords:
adenovirus; gene transfer; vector-mediated direct cytotoxicity; acute inflammation; chronic inflammation; dose response;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Lowenstein, PR Univ Manchester, Sch Med, Mol Med & Gene Therapy Unit, Room1-302,StopfordBldg,Oxford Rd, Manchester M13 9PT, Lancs, England Univ Manchester Room 1-302,Stopford Bldg,Oxford Rd Manchester Lancs England M13 9PT
Citazione:
C.E. Thomas et al., "Acute direct adenoviral vector cytotoxicity and chronic, but not acute, inflammatory responses correlate with decreased vector-mediated transgene expression in the brain", MOL THER, 3(1), 2001, pp. 36-46

Abstract

The potential utility of adenoviruses for the treatment of chronic neurological disease is controversial due to reports of vector-associated toxicity, inflammation, and transient transgene expression. To focus upon the mechanism by which transgene expression is lost, we injected increasing doses [1x 10(6) to 1 x 10(9) infectious units (iu)] of a first-generation adenovirus vector expressing beta -galactosidase into the brains of immune-competent adult rats. Transgene expression was evaluated simultaneously with acute neuronal and glial cell cytotoxicity, and acute and chronic inflammation using immunohistochemistry, at 3 and 30 days post-vector administration. Our results show a clear threshold effect of viral dose upon the amount of transgene expression persisting by 30 days after vector administration. Below 10(8) iu, transgene expression remained stable over the 30-day period. Following infection of more than 10(8) iu, the extent of transgene expression at30 days was inversely correlated with increasing viral dose. The severity of acute inflammation increased proportionally with increasing vector dose from 10(6) to 10(9) infectious units. In contrast, acute vector-mediated cytotoxicity and chronic inflammation were observed only above the threshold level of vector dose. Above 10(8) iu both the extent of the acute toxicity and the severity of the chronic inflammation were inversely correlated withtransgene expression at 30 days. Thus, our data suggest that both an acuteloss of cells through direct vector-mediated toxicity and the elicitation of chronic inflammation (but not acute inflammation) may account for the decline In transduction persistence at high vector doses.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/02/20 alle ore 13:06:41