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Titolo:
Linear DNAs concatemerize in vivo and result in sustained transgene expression in mouse liver
Autore:
Chen, ZY; Yant, SR; He, CY; Meuse, L; Shen, S; Kay, MA;
Indirizzi:
Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA Stanford UnivStanford CA USA 94305 , Dept Pediat, Stanford, CA 94305 USA Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA Stanford Univ Stanford CA USA 94305 d, Dept Genet, Stanford, CA 94305 USA Univ Washington, Mol & Cellular Biol Program, Seattle, WA 98105 USA Univ Washington Seattle WA USA 98105 Biol Program, Seattle, WA 98105 USA
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 3, volume: 3, anno: 2001,
pagine: 403 - 410
SICI:
1525-0016(200103)3:3<403:LDCIVA>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
RECOMBINANT ADENOASSOCIATED VIRUS; HEPATOCYTES IN-VIVO; STRAND BREAK REPAIR; HUMAN FACTOR-IX; PLASMID DNA; GENE-TRANSFER; INTERMOLECULAR RECOMBINATION; HUMAN ALPHA-1-ANTITRYPSIN; LIGASE-IV; TRANSDUCTION;
Keywords:
gene therapy; liver; hemophilia; factor IX; alpha 1-antitrypsin; nonviral; AAV;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Kay, MA Stanford Univ, Sch Med, Dept Pediat, 300 Pasteur Dr,Room G305, Stanford, CA 94305 USA Stanford Univ 300 Pasteur Dr,Room G305 Stanford CA USA 94305 5 USA
Citazione:
Z.Y. Chen et al., "Linear DNAs concatemerize in vivo and result in sustained transgene expression in mouse liver", MOL THER, 3(3), 2001, pp. 403-410

Abstract

The short duration of transgene expression remains a major obstacle for the implementation of nonviral DNA vectors in clinical gene therapy trials. Here, we demonstrate stable, long-term transgene expression in vivo by transfecting a linear DNA expression cassette (LDNA) into mouse liver. Interestingly, despite similar quantities and cellular distribution of injected DNAsin their livers, mice receiving LDNA encoding human alpha1-antitrypsin (hAAT) expressed approximately 10- to 100-fold more serum hAAT than mice injected with closed circular (cc) DNA for a period of 9 months (length of study). Furthermore, when a linear human factor IX expression cassette was delivered to factor lX-deficient mice, sustained serum concentrations of more than 4 mug/ml (80% of normal) of the human clotting factor and correction of the bleeding diathesis were obtained. Southern blot analyses indicate that,unlike ccDNA, LDNA rapidly formed large, unintegrated concatemers in vivo,suggesting that transgene persistence from plasmid-based vectors was influenced by the structure of the vector in transfected cells. No differences in transgene expression or DNA molecular structures were observed when AAV ITRs were included to flank the hAAT expression cassette in both ccDNA- and LDNA-treated animals. Linear DNA transfection provides an approach for achieving long-term expression of a transgene in vivo.

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Documento generato il 18/02/20 alle ore 05:35:25