Highly potent MyoAAV4A vector reverses GSD III pathology in aged mice and enables long-term muscle disease correction in young adult mice.

We recently reported a 6-week study in 3-month-old glycogen storage disorder (GSD) IIIa mice demonstrating that a myotropic AAV vector (MyoAAV4A-Dual-Pull) expressing a bacterial glycogen debranching enzyme (pullulanase) under the control of an immunotolerizing dual promoter achieved markedly higher transduction efficiency and superior glycogen clearance efficacy in cardiac and skeletal muscle compared with the AAV9-Dual-Pull vector. In the present study, we evaluated the efficacy of MyoAAV4A-Dual-Pull in aged GSD IIIa mice and assessed its therapeutic durability in young adult GSD IIIa mice. Intravenous injection of the MyoAAV4A-Dual-Pull (5 × 1012 vg/kg) into 13-month-old male and female GSD IIIa mice significantly reduced glycogen accumulation in the liver, heart, and skeletal muscle and reversed hepatic and muscular dysfunctions 3 months after vector administration. Moreover, treatment of 3-month-old male and female GSD IIIa mice with MyoAAV4A-Dual-Pull (5 × 1012 vg/kg) resulted in sustained pullulanase expression and significant glycogen reduction in the heart and quadriceps, accompanied by improved muscle function 9 months after vector administration. Our data demonstrate that MyoAAV4A-Dual-Pull effectively reverses disease phenotypes in aged GSD IIIa mice and provides durable muscle correction in young adult mice, supporting the development of a persistent and effective AAV gene therapy for GSD III.