33. Systemic Delivery of AAV8/DC190-GAA to Pompe Mice Normalizes Muscle Pathology and Corrects Motor Function Deficits

Abstract

Pompe disease, a lysosomal storage disorder, is generally known for it's characteristic degenerative myopathy. Massive accumulation of glycogen in lysosomes of striated and smooth muscle due to a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) results in muscle weakness and cardiorespiratory failure. In severely affected patients glycogen also accumulates in the central and peripheral nervous systems. Previously we demonstrated that systemic administration of AAV8/DC190-GAA to Pompe mice generated high circulating levels of GAA and reduced glycogen storage in cardiac and skeletal muscle to near normal levels. The current study was designed to determine if these effects on the viscera would be sufficient to prevent the loss of muscle strength and coordination shown to develop over time in the Pompe mouse. Since the GAA secreted into the blood should not cross the bloodbrain bloodbrain barrier, this study should also clarify the functional significance of peripheral and CNS glycogen storage in the Pompe mouse model. Two different concentrations of AAV8/DC190-GAA were injected into the tail vein of 10-week-old male Pompe mice. Treated Pompe mice, as well as vehicle-treated Pompe and B6129SF2/J normal control mice, were tested for their ability to perform in a battery of behavioral tests. Tests designed to measure muscle strength and coordination included accelerating and rocking Rota-rod, wire hang, and foot fault. As expected, the performance of the vehicle-treated Pompe mice declined over time when compared to wild type mice. In contrast the performance of AAV-treated Pompe mice was significantly improved over that of vehicle-treated Pompe mice, and was similar to normal mice. There was no significant difference between the two AAV8 dosing groups in any test except the wire hang. In this test the performance of the lower dose treatment group declined at the later time points. Severely affected patients rapidly accumulate glycogen, and infants are often not diagnosed until they show obvious myotonia. To model the treatment of this patient population, we administered AAV8/DC190-GAA to 10-month-old Pompe mice, an age at which they display significant muscle pathology and motor function decline. Mice treated at this advanced stage of the disease showed a partial recovery of muscle function, but performance was not normalized despite high circulating levels of GAA. We are currently measuring glycogen levels and studying the histopathology of muscle and CNS tissues from the mice in these studies. In summary, we have shown that systemic gene therapy treatment is capable of preventing degenerative myopathy and preserving motor function in Pompe mice, but is less effective in animals with pre-existing pathology.