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Publication Detail
Potential limits of AAV-based gene therapy with the use of new transgenes expressing factor IX fusion proteins
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Le Quellec S, Dane A, Enjolras N, McIntosh J, Rosales C, Negrier C, Nathwani A
  • Publication date:
    06/12/2018
  • Journal:
    Haemophilia
  • Status:
    Accepted
  • Print ISSN:
    1351-8216
Abstract
© 2018 John Wiley & Sons Ltd Introduction: The variety of treatment for haemophilia B (HB) has recently improved with the emergence of both AAV-based gene therapy and bioengineered human factor IX (hFIX) molecules with prolonged half-life due to fusion to either albumin (Alb) or immunoglobulin Fc fragment (Fc). Aim: Adeno-associated viral vectors (AAV) mediating expression of hFIX-Alb and hFIX-Fc fusion proteins was investigated for gene therapy of HB to explore if their extended half-life translates to higher plasma levels of FIX. Methods: Single-stranded cross-packaged AAV2/8 vectors expressing hFIX-Alb, hFIX-Fc and hFIX were evaluated in vitro, and in mice. Results: Both hFIX-Alb and hFIX-Fc fusion proteins were synthesized and expressed as single chains of expected size following AAV-mediated gene transfer in vitro and in vivo. The procoagulant properties of these hFIX-fusion proteins were comparable to wild-type hFIX. However, their expression levels were threefold lower than wild-type hFIX in vivo most likely due to inefficient secretion. Conclusion: This, the first, evaluation of hFIX-fusion proteins in the context of AAV gene transfer suggests that the hFIX-fusion proteins are secreted inefficiently from the liver, thus preventing their optimal use in gene therapy approaches.
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