Abstract
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 α-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.
Authors
Naresh K. Meena, Davide Randazzo, Nina Raben, Rosa Puertollano
Figure 10
Systemic gene transfer restores glycogen accumulation to normal levels in the brain after long-term treatment at an intermediate vector dose.
