Impaired clearance of accumulated lysosomal glycogen in advanced Pompe disease despite high‐level vector‐mediated transgene expression

Background Infantile‐onset glycogen storage disease type II (GSD‐II; Pompe disease; MIM 232300) causes death early in childhood from cardiorespiratory failure in the absence of effective treatment, whereas late‐onset Pompe disease causes a progressive skeletal myopathy. The limitations of enzyme replacement therapy could potentially be addressed with adeno‐associated virus (AAV) vector‐mediated gene therapy. Methods AAV vectors containing tissue‐specific regulatory cassettes, either liver‐specific or muscle‐specific, were administered to 12‐ and 17‐month‐old Pompe disease mice to evaluate the efficacy of gene therapy in advanced Pompe disease. Biochemical correction was evaluated through acid α‐glucosidase (GAA) activity and glycogen content analyses of the heart and skeletal muscle. Western blotting, urinary biomarker, and Rotarod performance were evaluated after vector administration. Results The AAV vector containing the liver‐specific regulatory cassette secreted high‐level human GAA into the blood and corrected glycogen storage in the heart and diaphragm. The biochemical correction of the heart and diaphragm was associated with efficacy, as reflected by increased Rotarod performance; however, the clearance of glycogen from skeletal muscles was relatively impaired compared to in younger Pompe disease mice. An alternative vector containing a muscle‐specific regulatory cassette transduced skeletal muscle with high efficiency, but also failed to achieve complete clearance of accumulated glycogen. Decreased transduction of the heart and liver in older mice, especially in females, was implicated as a cause for reduced efficacy in advanced Pompe disease. Conclusions The impaired efficacy of AAV vector‐mediated gene therapy in old Pompe disease mice emphasizes the need for early treatment to achieve full efficacy. Copyright © 2009 John Wiley & Sons, Ltd.