Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-alpha-glucosidase

This report demonstrates that a single intravenous administration of a gene therapy vector can potentially result in the correction of all affected mu scles in a mouse model of a human genetic muscle disease. These results wer e achieved by capitalizing both on the positive attributes of modified aden ovirus-based vectoring systems and receptor-mediated lysosomal targeting of enzymes. The muscle disease treated, glycogen storage disease type II, is a lysosomal storage disorder that manifests as a progressive myopathy, seco ndary to massive glycogen accumulations in the skeletal and/or cardiac musc les of affected individuals, We demonstrated that a single intravenous admi nistration of a modified Ad vector encoding human acid alpha-glucosidase (G AA) resulted in efficient hepatic transduction and secretion of high levels of the precursor GAA proenzyme into the plasma of treated animals. Subsequ ently, systemic distribution and uptake of the proenzyme into the skeletal and cardiac muscles of the GAA-knockout mouse was confirmed. As a result, s ystemic decreases (and correction) of the glycogen accumulations in a varie ty of muscle tissues was demonstrated. This model can potentially be expand ed to include the treatment of other lysosomal enzyme disorders. Lessons le arned from systemic genetic therapy of muscle disorders also should have im plications for other muscle diseases, such as the muscular dystrophies.