Phase I study of liver depot gene therapy in late-onset Pompe disease

Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid a-glucosidase (GAA) production. We report initial safety and bioactivity of the first dose (1.6 x 1012 vector genomes/kg) cohort (n = 3) in a 52-week open-label, single-dose, dose -escala-tion study (NCT03533673) in patients with late-onset Pompe disease (LOPD). Subjects discontinued biweekly ERT after week 26 based on the detection of elevated serum GAA activity and the absence of clinically significant declines per protocol. Prednisone (60 mg/day) was administered as immunoprophy-laxis through week 4, followed by an 11-week taper. All subjects demonstrated sustained serum GAA activities from 101% to 235% of baseline trough activity 2 weeks following the preced-ing ERT dose. There were no treatment-related serious adverse events. No subject had anti-capsid T cell responses that decreased transgene expression. Muscle biopsy at week 24 revealed unchanged muscle glycogen content in two of three subjects. At week 52, muscle GAA activity for the cohort was significantly increased (p < 0.05). Overall, these initial data sup-port the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease.

Automated summary

An initial study on gene therapy for late-onset Pompe disease showed that using an adeno-associated virus serotype 8 vector was safe and effective, leading to increased activity of acid a-glucosidase in the muscles of patients, indicating the potential of this treatment for clinical use in Pompe disease.