Advances in Gene Therapy Clinical Trials for Hemophilia Care.

Abstract

Gene therapy has revolutionized the therapeutic landscape for hemophilia A and B, offering the prospect for persistent endogenous production of coagulation factors VIII and IX. Recent advances in adeno-associated virus (AAV)-mediated gene transfer, particularly the approvals of valoctocogene roxaparvovec (Roctavian) and etranacogene dezaparvovec (Hemgenix), mark significant milestones in hemophilia care. This mini-review synthesizes emerging clinical data from phase I-III trials published between 2022 and 2025, emphasizing efficacy, durability, and immunogenicity profiles of leading AAV-based therapies. Innovations in vector design, such as liverspecific promoters, codon-optimized constructs, and novel capsids (e.g., AAVhu37, AAVrh10, AAV-Spark100), have improved transgene expression and expanded eligibility. Despite notable success, challenges persist, including immune-mediated transaminitis, declining factor activity over time, particularly in hemophilia A, and limitations posed by preexisting neutralizing antibodies. Additionally, CRISPR-Cas9 and non-viral delivery systems are emerging as complementary strategies, potentially enhancing therapeutic precision and overcoming AAV-related barriers. The review also addresses the critical need for equitable access and scalable production models to ensure global availability of gene therapies. With ongoing innovation and multidisciplinary collaboration, gene therapy is poised to transition from experimental intervention to mainstream curative care in hemophilia and other hematologic diseases.