Systemically administered gene therapy is under development for the treatment of Pompe disease, an inherited lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. We evaluated recombinant AAV9 vectors expressing GAA driven by the minimal G6PC promoter (AAV9-G6PC.GAA) and by a hybrid CRM4-G6PC promoter (AAV9-MyoG6PC.GAA) and intravenously administered the vectors (1 × 1013 vg/kg) to adult Gaa knockout (Gaa-KO) mice that were analyzed 3 or 12 weeks later. In the 3-week experiment, both AAV vector treatments led to significant increase in GAA activity in the liver, heart, quadriceps, gastrocnemius, and diaphragm. The AAV9-MyoG6PC.GAA treated mice had significantly higher GAA activities in the heart and limb muscles than the AAV9-G6PC.GAA treated mice. Both AAV9-G6PC.GAA and AAV9-MyoG6PC.GAA vectors significantly cleared glycogen accumulation in the heart, quadriceps, gastrocnemius, and diaphragm. AAV9-G6PC.GAA-treated mice had slightly decreased glycogen content in the brain, in comparison with untreated mice. AAV9-MyoG6PC.GAA was further evaluated in a 12-week study. GAA activities were significantly increased in the liver, heart, and skeletal muscles of AAV9-MyoG6PC.GAA-treated mice. Glycogen contents were significantly decreased by the AAV9-MyoG6PC.GAA treatment in the heart and skeletal muscle of male mice, accompanied by the improvement of muscle functions in the grip strength test. However, female mice had an attenuated response with lower GAA activity and higher glycogen content in comparison with males, which correlated with lower plasma GAA activity. Anti-GAA antibody responses were not detected in any AAV-treated mice. In summary, adding a muscle enhancer to the G6PC minimal promoter that drives high-level GAA expression in liver increased efficacy in the heart and skeletal muscle without provoking antibody responses in Gaa-KO mice.
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