In vivo genome-editing therapy for Duchenne muscular dystrophy: Preclinical studies and first-in-human trial.

Systemic AAV9-delivered hfCas12Max in humanized Duchenne muscular dystrophy mice achieved targeted genome editing, partial dystrophin restoration, and improved muscle function.

• Why it matters: The work addresses the need for in vivo muscle genome editing in DMD and highlights immunologic risks and a narrow therapeutic window for systemic AAV-CRISPR therapies.
• What they did: In an open-label, dose-escalation first-in-human trial (NCT06594094), post-treatment muscle biopsies assessed hfCas12Max-mediated editing and dystrophin expression, with safety evaluated across dose levels.
• The result: At 1.0 × 10^14 vg/kg, one participant had a treatment-related fatal serious adverse event with marked complement activation and systemic cytokine response shortly after dosing.