First-in-human case report: AAV9-hGAA gene therapy for a patient with infantile-onset Pompe disease.

Background: The classic infantile-onset Pompe disease (IOPD) is characterized by cardiac hypertrophy, respiratory insufficiency, and rapidly progressive muscle weakness due to the acid alpha-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) is the current approach for IOPD, but it entails several limitations. Aiming to overcome the limited efficiency of ERT, we developed AAV-associated gene therapy for IOPD patients. Method: One IOPD patient received a single intravenous dose of GC301, a recombinant adeno-associated virus 9 (rAAV9) expressing the human GAA (rAAV-hGAA). During the follow-up, safety was accessed by the physical examinations, cardiac and laboratory evaluations. GAA activity, the titers of serum antibodies to AAV9 and GAA, and motor development were monitored regularly. Result: The infant showed significant improvements in motor milestones. The GAA enzyme activity increased to the normal range. The cardiac function improved notably. Conclusion: In patient with IOPD, a single intravenous AAV9-hGAA gene therapy improved the clinical outcomes remarkably. The trial is still ongoing, the safety of this gene therapy and the long-term clinical benefit remain to be monitored for months and years to come.