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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
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
Blood, Volume 107, No. 7, Year 2006
Notification
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Description
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. © 2006 by The American Society of Hematology.
Authors & Co-Authors
Nathwani, Amit Chunilal
United Kingdom, London
University College London
Waddington, Simon N.
Unknown Affiliation
Tuddenham, Edward G.D.
Unknown Affiliation
McIntosh, Jenny H.
Unknown Affiliation
Davidoff, Andrew M.
Unknown Affiliation
Statistics
Citations: 336
Authors: 5
Affiliations: 1
Identifiers
Doi:
10.1182/blood-2005-10-4035
ISSN:
00064971
Research Areas
Genetics And Genomics