Highlights From the ASGCT 2026 Annual Meeting
Evolution Directed Gene Engineered (EDGE) Gain-of-Function Factor VIII Variants Enhance Gene Therapy for Hemophilia A
Presenting Author: Adam Dyer, PhD
Adam Dyer,1 Lucas Van Gorder,1 Yani Suber,1 Julia Chau,1 Reilly Peng,1 Benjamin Samelson-Jones1
Children's Hospital of Philadelphia, Perelman Center for Cellular and Molecular Therapeutics (CCMT), Philadelphia, United States
UPenn Hematology T32 Grant
National Bleeding Disorder Foundation
NIH/NHLBI: P01HL139420
At ASGCT 2026, a novel approach to improve hemophilia A gene therapy was presented using engineered FVIII variants with enhanced specific activity. An Evolution Directed Gene Engineering (EDGE) screen identified substitutions at lysine 659 (K659M and K659V) that increased FVIII activity more than 5-fold compared with wild-type FVIII. Mechanistic studies demonstrated that the enhanced activity resulted from improved FVIIIa–FIXa interactions within the intrinsic Xase complex, without altering normal regulatory pathways.
In hemophilia A mouse models, these variants restored hemostasis at approximately half the dose required for wild-type FVIII. When delivered by AAV gene therapy, the variants produced 3- to 15-fold higher circulating FVIII activity than wild-type FVIII. These findings suggest that hyperactive FVIII variants could help overcome current limitations of hemophilia A gene therapy by achieving greater hemostatic efficacy at lower expression levels.
Figure Legend: a) Site saturation of K659 by in vitro transfection (n ≥ 2). Activity measured by aPTT, FVIII concentration measured by anti-FVIII ELISA. Specific activity presented as fold change vs FVIII (K). b) Blood loss resulting from the tail vein transection injury model post rFVIII administration. c) Circulating FVIII activity 8 weeks post vector administration. *P < 0.05, **P < 0.005.
