Engineered coagulation factor VIII with enhanced secretion and coagulation potential for hemophilia A gene therapy.

ABSTRACT:

Abstract

The major challenges of gene therapy for hemophilia A using adeno-associated virus (AAV) vectors are reducing vector doses and the long-term maintenance of stable factor VIII (FVIII). In this study, we developed engineered human B-domain-deleted FVIIIs (FVIIISQ) with enhanced secretion and coagulation potential. Intracellular accumulation was markedly reduced in some engineered FVIIISQ, resulting in reduced unfolded protein responses. The administration of AAV vectors carrying engineered FVIIISQ to hemophilia A mice resulted in ∼8-fold higher FVIII activity and 4-fold higher FVIII antigen levels compared with wild-type FVIIISQ administration. The specific FVIII activity of the engineered FVIIISQ was 3.6 times higher than that of the wild-type FVIIISQ, and its binding to ac

SUBMITTER: Kashiwakura Y 

PROVIDER: S-EPMC12883863 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature