Cases of High-Titer Inhibitor Formation After AAV Gene Therapy for Hemophilia A.

High-titer FVIII inhibitors developed in two hemophilia A patients after ASC618 gene therapy, remaining nearly two years post-infusion despite declining titers.

• Why it matters: Immunogenicity limits the durability of AAV-based gene therapies for hemophilia A, and understanding inhibitor formation is crucial for improving safety and efficacy.
• What they did: Two patients in a phase 1/2 trial received ASC618, a bioengineered FVIII transgene with a human/porcine hybrid construct, and both developed high-titer inhibitors despite extensive prior FVIII exposure.
• The result: The cases underscore the importance of immunogenicity assessment for bioengineered transgenes in gene therapy, informing future development to mitigate inhibitor risks.