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

DOI PDF 被引用文献9件
  • Amit C. Nathwani
    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.
  • John T. Gray
    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.
  • Catherine Y. C. Ng
    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.
  • Junfang Zhou
    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.
  • Yunyu Spence
    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.
  • Simon N. Waddington
    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.
  • Edward G. D. Tuddenham
    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.
  • Geoffrey Kemball-Cook
    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.
  • Jenny McIntosh
    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.
  • Mariette Boon-Spijker
    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.
  • Koen Mertens
    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.
  • 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.

抄録

<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>

収録刊行物

  • Blood

    Blood 107 (7), 2653-2661, 2006-04-01

    American Society of Hematology

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