ArticlebioRxiv : the preprint server for biology2024
Overcoming Hemophilia A Gene Therapy Limitations with an Enhanced Function Factor VIII Variant.
Article in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Durable factor VIII (FVIII) expression that normalizes hemostasis is an unrealized goal of hemophilia A adeno-associated virus (AAV)-mediated gene therapy. Trials with initial normal FVIII activity observed unexplained year-over-year declines in expression while others reported low-level, stable FVIII expression inadequate to restore normal hemostasis. Here we demonstrate that mice recapitulate FVIII expression-level-dependent loss of plasma FVIII levels due to declines in vector copy number. We show that an enhanced function FVIII variant (FVIII-R336Q/R562Q; FVIII-QQ), resistant to inactivation by protein C, normalizes hemostasis at below-normal expression levels without evidence of prothrombotic risk in hemophilia A mice. These data support that FVIII-QQ may restore normal FVIII function at low-levels of expression to permit durability using low AAV vector doses to minimize dose-dependent AAV toxicities. This work informs the mechanism of FVIII durability after AAV gene transfer and supports that incorporating the FVIII-QQ transgene may safely overcome current hemophilia A gene therapy limitations.
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