How Close Are We to Achieving Durable and Efficacious Gene Therapy for Hemophilia A and B?

Authors: Sosnowska-Sienkiewicz, P; Januszkiewicz-Lewandowska, D

Affiliations: Med Univ Warsaw, Dept Pediat Surg, Zwirki & Wigury 63A St, PL-02091 Warsaw, Poland; Poznan Univ Med Sci, Dept Pediat Oncol Hematol & Transplantol, Ul Fredry 10, PL-61701 Poznan, Poland

Publication: Genes; 2025 ; 16

ABSTRACT: Hemophilia, an X-linked recessive bleeding disorder, results from mutations in the F8 or F9 genes, leading to factor VIII (hemophilia A) or factor IX (hemophilia B) deficiency. While conventional treatment relies on regular factor replacement therapy, gene therapy has emerged as a promising alternative, offering the potential for sustained endogenous factor production after a single administration. This review provides an in-depth analysis of recent advances in gene therapy for both hemophilia A and B, with a focus on AAV-mediated liver-directed approaches and other approved modalities. Key limitations-such as vector immunogenicity, hepatic toxicity, waning transgene expression, and limited re-dosing capacity-are discussed. Additional gene delivery platforms, including lentiviral and retroviral vectors, genome editing techniques (e.g., CRISPR/Cas9), and non-viral systems like transposons and lipid nanoparticles, are also examined. Although gene therapy for hemophilia B demonstrates greater clinical durability, hemophilia A presents unique challenges due to factor VIII’s size, poor expression efficiency, and the need for higher vector doses. Future efforts will focus on overcoming immune barriers, improving delivery technologies, and developing approaches suitable for pediatric patients and individuals with pre-existing immunity. This review provides not only a descriptive overview but also a critical comparison of gene therapy approaches for hemophilia A and B. We emphasize that the durability of response is currently superior in hemophilia B, whereas hemophilia A still faces unique barriers, including declining FVIII expression and higher immunogenicity. By analyzing cross-platform challenges (AAV, lentiviral, CRISPR, and emerging LNPs), we highlight the most promising strategies for overcoming these limitations and provide a forward-looking perspective on the future of gene therapy.