Next-generation Factor VIII Variants to Improve Gene Therapy for Hemophilia A

Speakers: Ben Samelson-Jones, MD, PhD, Children's Hospital of Philadelphia | Halli Benasutti, PhD, NBDF

Current gene therapy approaches for hemophilia A have been limited by suboptimal durability and inability to sustain factor (F) VIII activity in the therapeutic range. These limitations are thought to result, in part, from cellular toxicity associated with high-level FVIII expression. To overcome this barrier, we developed gain-of-function FVIII variants with increased specific activity, enabling higher functional activity at lower protein expression levels. These variants enhance FVIIIa–FIXa interactions without altering activation or inactivation kinetics and demonstrate improved thrombin generation and hemostatic efficacy in vitro and in hemophilia A mice. In AAV-mediated gene therapy studies, vectors achieved significantly higher FVIII activity levels than wild-type FVIII, supporting their potential to improve therapeutic durability while mitigating dose-related toxicity. 

Collectively, these findings support high-specific-activity FVIII variants as a promising next-generation strategy to achieve sustained, clinically meaningful FVIII activity levels without increasing thrombogenicity or immunogenicity.