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Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B. | LitMetric

AI Article Synopsis

  • - The study focused on using adeno-associated viral (AAV) vectors to deliver the factor IX (FIX) gene directly to skeletal muscles in dogs with hemophilia B, showing better results than previous direct muscle injections.
  • - An intravascular delivery system combined with temporary immunosuppression resulted in significant and lasting therapeutic levels of FIX, leading to fewer spontaneous bleeding episodes in treated dogs.
  • - The approach preserved the effectiveness of AAV vectors, even in the presence of some antibodies, with none of the dogs developing inhibitors against the FIX protein, demonstrating a promising strategy for treating hemophilia B.

Article Abstract

Muscle represents an important tissue target for adeno-associated viral (AAV) vector-mediated gene transfer of the factor IX (FIX) gene in hemophilia B (HB) subjects with advanced liver disease. Previous studies of direct intramuscular administration of an AAV-FIX vector in humans showed limited efficacy. Here we adapted an intravascular delivery system of AAV vectors encoding the FIX transgene to skeletal muscle of HB dogs. The procedure, performed under transient immunosuppression (IS), resulted in widespread transduction of muscle and sustained, dose-dependent therapeutic levels of canine FIX transgene up to 10-fold higher than those obtained by intramuscular delivery. Correction of bleeding time correlated clinically with a dramatic reduction of spontaneous bleeding episodes. None of the dogs (n = 14) receiving the AAV vector under transient IS developed inhibitory antibodies to canine FIX; transient inhibitor was detected after vector delivery without IS. The use of AAV serotypes with high tropism for muscle and low susceptibility to anti-AAV2 antibodies allowed for efficient vector administration in naive dogs and in the presence of low- but not high-titer anti-AAV2 antibodies. Collectively, these results demonstrate the feasibility of this approach for treatment of HB and highlight the importance of IS to prevent immune responses to the FIX transgene product.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890180PMC
http://dx.doi.org/10.1182/blood-2009-12-261156DOI Listing

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