Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver
Autore:
Tao, NJ; Gao, GP; Parr, M; Johnston, J; Baradet, T; Wilson, JM; Barsoum, J; Fawell, SE;
Indirizzi:
Biogen Inc, Cambridge, MA 02142 USA Biogen Inc Cambridge MA USA 02142Biogen Inc, Cambridge, MA 02142 USA Univ Penn, Med Ctr, Inst Human Gene Therapy, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 e Therapy, Philadelphia, PA 19104 USA Wistar Inst, Philadelphia, PA 19104 USA Wistar Inst Philadelphia PA USA 19104 ar Inst, Philadelphia, PA 19104 USA
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 1, volume: 3, anno: 2001,
pagine: 28 - 35
SICI:
1525-0016(200101)3:1<28:SOAVBK>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
MEDIATED GENE-TRANSFER; VIRAL-ANTIGENS; IN-VIVO; IMMUNE-RESPONSES; MOUSE-LIVER; FACTOR-IX; EXPRESSION; HEPATOCYTES; TOXICITY; MICE;
Keywords:
adenovirus; gene therapy; Kupffer; dose response; interferon-beta;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
34
Recensione:
Indirizzi per estratti:
Indirizzo: Fawell, SE Biogen Inc, 12 Cambridge Ctr, Cambridge, MA 02142 USA Biogen Inc 12 Cambridge Ctr Cambridge MA USA 02142 MA 02142 USA
Citazione:
N.J. Tao et al., "Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver", MOL THER, 3(1), 2001, pp. 28-35

Abstract

Systemic administration of a recombinant adenovirus encoding the human interferon-beta gene (H5.110CMVhFN-beta) results in transduction of hepatocytes and detectable circulating levels of IFN-beta protein. In preclinical studies in mice, we noticed a distinctly nonlinear dose response, with low levels of virus (1-3 x 10(10) viral particles) yielding barely detectable levels of IFN-beta but with a higher viral dose (1 x 10(11) particles) resulting in disproportionately high IFN-beta levels. Further studies showed that transgene expression levels from low viral doses could be dramatically enhanced by coadministering an unrelated recombinant adenovirus (H5.110CMVlacZ),suggesting that there was a viral dose threshold effect for efficient viral transduction and/or IFN-beta expression. This enhancement of reporter expression by a nonreporter adenovirus, effective upon coadministration, was further enhanced by preadministration of H5.110CMVlacZ (up to 8 h), but was ineffective if the helper virus was administered as little as 5 min after the H5.110CMVhIFN-beta reporter virus. Our data suggest that the reticuloendothelial system plays a role in this threshold effect, such that low doses of virus are efficiently taken up by the RES/Kupffer cells without leading to appreciable transgene expression, whereas high doses saturate these cells and are able to productively transduce hepatocytes. A better understanding of this phenomenon could have an impact on gene therapy clinical trial safety and efficacy.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/01/20 alle ore 22:39:16