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

We report the preclinical and early clinical evaluation of in vivo genome editing for Duchenne muscular dystrophy (DMD), delivered via a single AAV9 vector. In humanized DMD mice, systemic administration achieved targeted genome editing, partial dystrophin restoration, and improved muscle function. In non-human primates, efficient on-target editing was achieved with no dose-limiting toxicity identified under the conditions tested. In an open-label, dose-escalation, first-in-human clinical trial (NCT06594094), post-treatment muscle biopsies provided early molecular evidence of hfCas12Max-mediated genome editing and detectable dystrophin expression in participants with DMD. However, at the higher dose level (1.0 × 10¹⁴ vg/kg), one participant experienced a treatment-related fatal serious adverse event, characterized by marked complement activation and systemic cytokine response shortly after dosing. This work provides initial human proof-of-concept for muscle genome editing while crucially highlighting the critical role of immunologic risks and the narrow therapeutic window of systemic adeno-associated virus (AAV)-CRISPR therapies, underscoring the need to develop safer dosing and immunomodulation strategies.