Pre-clinical evaluation of an enhanced-function factor VIII variant for durable hemophilia A gene therapy in male mice

Anna R. Sternberg, Cristina Martos-Rus, Robert J. Davidson, Xueyuan Liu and Lindsey A. George ()
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Anna R. Sternberg: the Children’s Hospital of Philadelphia
Cristina Martos-Rus: the Children’s Hospital of Philadelphia
Robert J. Davidson: the Children’s Hospital of Philadelphia
Xueyuan Liu: the Children’s Hospital of Philadelphia
Lindsey A. George: the Children’s Hospital of Philadelphia

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Durable factor VIII expression that normalizes hemostasis is an unrealized goal of hemophilia A adeno-associated virus-mediated gene therapy. Trials with initially normal factor VIII activity observed unexplained year-over-year declines in expression while others reported low-level, stable expression inadequate to restore normal hemostasis. Here we demonstrate that male mice recapitulate expression-level-dependent loss of factor VIII levels due to declines in vector copy number. We show that an enhanced function factor VIII variant (factor VIII-R336Q/R562Q), resistant to activated protein C-mediated inactivation, normalizes hemostasis at below-normal expression without evidence of prothrombotic risk in male hemophilia A mice. These data support that factor VIII-R336Q/R562Q may restore normal factor VIII function at low levels of expression to permit durability using low vector doses to minimize dose-dependent adeno-associated virus toxicities. This work informs the mechanism of factor VIII durability after gene transfer and supports that factor VIII-R336Q/R562Q may safely overcome current hemophilia A gene therapy limitations.

Date: 2024
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DOI: 10.1038/s41467-024-51296-8

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