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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2653-2661.
Prepublished online as a Blood First Edition Paper on December 1, 2005; DOI 10.1182/blood-2005-10-4035.
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GENE THERAPY
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
Amit C. Nathwani,
John T. Gray,
Catherine Y. C. Ng,
Junfang Zhou,
Yunyu Spence,
Simon N. Waddington,
Edward G. D. Tuddenham,
Geoffrey Kemball-Cook,
Jenny McIntosh,
Mariette Boon-Spijker,
Koen Mertens, and
Andrew M. Davidoff
From the Department of Haematology, University College London and the National Blood Service, London, United Kingdom; the Division of Experimental Hematology and the Department of Surgery, St Jude Children's Research Hospital, Memphis, TN; Gene Therapy Research and Haemostasis and Thrombosis Research Groups, Imperial College London, London, United Kingdom; Sanquin Research, Amsterdam, the Netherlands; and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
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 x 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.
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