Nathwani, Amit C.;
Gray, John T.;
Ng, Catherine Y. C.;
Zhou, Junfang;
Spence, Yunyu;
Waddington, Simon N.;
Tuddenham, Edward G. D.;
Kemball-Cook, Geoffrey;
McIntosh, Jenny;
Boon-Spijker, Mariette;
Mertens, Koen;
Davidoff, Andrew M.
Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver
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Medientyp:
E-Artikel
Titel:
Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver
Beteiligte:
Nathwani, Amit C.;
Gray, John T.;
Ng, Catherine Y. C.;
Zhou, Junfang;
Spence, Yunyu;
Waddington, Simon N.;
Tuddenham, Edward G. D.;
Kemball-Cook, Geoffrey;
McIntosh, Jenny;
Boon-Spijker, Mariette;
Mertens, Koen;
Davidoff, Andrew M.
Erschienen:
American Society of Hematology, 2006
Erschienen in:Blood
Sprache:
Englisch
DOI:
10.1182/blood-2005-10-4035
ISSN:
0006-4971;
1528-0020
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Transduction with recombinant adeno-associated virus (AAV) vectors is limited by the need to convert its single-stranded (ss) genome to transcriptionally active double-stranded (ds) forms. For AAV-mediated hemophilia B (HB) gene therapy, we have overcome this obstacle by constructing a liver-restricted mini–human factor IX (hFIX) expression cassette that can be packaged as complementary dimers within individual AAV particles. Molecular analysis of murine liver transduced with these self-complementary (sc) vectors demonstrated rapid formation of active ds-linear genomes that persisted stably as concatamers or monomeric circles. This unique property resulted in a 20-fold improvement in hFIX expression in mice over comparable ssAAV vectors. Administration of only 1 × 1010 scAAV particles led to expression of hFIX at supraphysiologic levels (8I U/mL) and correction of the bleeding diathesis in FIX knock-out mice. Of importance, therapeutic levels of hFIX (3%-30% of normal) were achieved in nonhuman primates using a significantly lower dose of scAAV than required with ssAAV. Furthermore, AAV5-pseudotyped scAAV vectors mediated successful transduction in macaques with pre-existing immunity to AAV8. Hence, this novel vector represents an important advance for hemophilia B gene therapy.</jats:p>