Gene Therapy for Hemophilia: From Basic Science to First Approvals of "One-and-Done" Therapies

Research conducted at the Indiana University School of Medicine has led to significant advancements in gene therapy for hemophilia. The study, published in Molecular Therapy, highlighted the emergence of AAV gene transfer to hepatocytes as a promising strategy for treating hemophilia A and B. Funded by the National Institutes of Health (NIH) and the Riley Children's Foundation, the research aimed to overcome obstacles in gene therapy, including pre-existing immunity, toxicities, and inter-patient variability. The study concluded that sustained partial to complete correction of coagulation has been achieved in patients, with some experiencing therapeutic factor levels for years without frequent injections.

Key Takeaways:

• The study findings provide a realistic path to gene therapy for hemophilia, starting from the mid-1990s, with disease correction achieved in small and large animal models.
• AAV gene transfer to hepatocytes has emerged as the most promising strategy, leading to multiple clinical trials and regulatory approvals for hemophilia B and A treatment.
• Researchers have overcome multiple obstacles, including pre-existing immunity to AAV capsids, toxicities, inter-patient variability, and difficulty in obtaining durable therapeutic expression of FVIII.
• Alternative approaches, such as in vivo gene editing and ex vivo gene therapies targeting hemopoietic cells, are in development.
• The study emphasizes the need for durable therapeutic expression of FVIII and the challenges associated with pre-existing immunity to AAV capsids.
• Researchers have achieved sustained partial to complete correction of coagulation for several years to an entire decade in patients, with observation ongoing.
• A hyperactive form of FIX improved efficacy in hemophilia B, and superior engineered variants of FVIII are emerging.

Statistics:

• Over 10 years, research has led to sustained partial to complete correction of coagulation, with some patients experiencing therapeutic factor levels for years.
• AAV gene transfer to hepatocytes has shown promise in treating hemophilia A and B, with multiple clinical trials and regulatory approvals.
• The study highlights the importance of overcoming pre-existing immunity to AAV capsids, with challenges remaining in obtaining durable therapeutic expression of FVIII.
• Alternative approaches, including in vivo gene editing and ex vivo gene therapies targeting hemopoietic cells, are in development.

Sources:

• Molecular Therapy, 2025;33(5):2015-2034
• Cell Press, 50 Hampshire St, Floor 5, Cambridge, MA 02139, USA. (Elsevier - www.elsevier.com; Molecular Therapy - www.journals.elsevier.com/molecular-therapy/)
• Indiana University School of Medicine, Herman Wells Ctr Pediat Res B, Indianapolis, IN 46202, United States.