AAV-mediated delivery of secreted acid a-glucosidase with enhanced uptake corrects neuromuscular pathology in Pompe mice

Gene therapy is under advanced clinical development for several lysosomal storage disorders. Pompe disease, a debilitating neuromuscular illness affecting infants, children, and adults with different severity, is caused by a deficiency of lysosomal glycogen-degrading enzyme acid & alpha;-glucosidase (GAA). Here, we demonstrated that adeno-associated virus-mediated (AAV-mediated) systemic gene transfer reversed glycogen storage in all key therapeutic targets - skeletal and cardiac muscles, the diaphragm, and the central nervous system - in both young and severely affected old Gaa- knockout mice. Furthermore, the therapy reversed secondary cellular abnormalities in skeletal muscle, such as those in autophagy and mTORC1/AMPK signaling. We used an AAV9 vector encoding a chimeric human GAA protein with enhanced uptake and secretion to facilitate efficient spread of the expressed protein among multiple target tissues. These results lay the groundwork for a future clinical development strategy in Pompe disease.

Automated summary

Gene therapy has shown potential in treating lysosomal storage disorders, such as Pompe disease, by reversing glycogen storage and improving cellular abnormalities. In a study, adeno-associated virus-mediated gene transfer successfully reversed glycogen storage in various target tissues and improved secondary cellular abnormalities in skeletal muscle. These findings lay the foundation for future clinical development in treating Pompe disease.