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

Author

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  • Anna R. Sternberg

    (the Children’s Hospital of Philadelphia
    the Children’s Hospital of Philadelphia
    Perelman School of Medicine at the University of Pennsylvania)

  • Cristina Martos-Rus

    (the Children’s Hospital of Philadelphia
    the Children’s Hospital of Philadelphia)

  • Robert J. Davidson

    (the Children’s Hospital of Philadelphia
    the Children’s Hospital of Philadelphia)

  • Xueyuan Liu

    (the Children’s Hospital of Philadelphia)

  • Lindsey A. George

    (the Children’s Hospital of Philadelphia
    the Children’s Hospital of Philadelphia
    Perelman School of Medicine at the University of Pennsylvania)

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.

Suggested Citation

  • Anna R. Sternberg & Cristina Martos-Rus & Robert J. Davidson & Xueyuan Liu & Lindsey A. George, 2024. "Pre-clinical evaluation of an enhanced-function factor VIII variant for durable hemophilia A gene therapy in male mice," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51296-8
    DOI: 10.1038/s41467-024-51296-8
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