Gene Therapy of Haemophilia: Current Status and Future Directions

Gene therapy represents a paradigm shift in haemophilia management, offering the potential for sustained factor expression and freedom from prophylactic infusions. Two adeno-associated virus (AAV)-based gene therapies are now approved. Long-term follow-up data demonstrate remarkable durability, with 13-year results showing sustained reductions in annualized bleeding rates in patients with haemophilia B. Outcomes differ between haemophilia A and B: factor VIII levels in haemophilia A decline after peaking, whereas factor IX expression in haemophilia B remains more stable. Recent analyses confirm significant reductions in bleeding rates and treatment requirements, along with well-characterized safety profiles. Liver toxicity remains the primary safety concern, with transaminase elevations typically responding to corticosteroids. Rare adverse events include one reported case of inhibitor development and very few thrombotic events. Reported malignancies to date have not been associated with gene therapy. Current limitations include eligibility restrictions due to preexisting neutralizing antibodies, immune responses to AAV capsids, and variable patient outcomes. These challenges may contribute to slower adoption despite regulatory approval. Emerging approaches such as CRISPR-Cas9 gene editing, high-active factor variants, and novel delivery systems are under investigation. Key implementation issues include outcome-based reimbursement, hub-and-spoke treatment models, and ensuring equitable global access.