GAA replacement improves respiratory muscle, neural, and alveolar pathology in the pompe mouse.

Pompe disease is a devastating neuromuscular disorder caused by mutations in the gene GAA. These mutations result in a deficiency of the enzyme acid α-glucosidase (GAA), leading to lysosomal glycogen accumulation in cardiac, skeletal, and smooth muscle, motor neurons, and alveolar epithelial cells. Respiratory failure due to neuromuscular weakness, recurrent aspiration pneumonia, and tracheo-bronchomalacia are the leading causes of morbidity and mortality in PD patients. Enzyme replacement therapy (ERT) is currently the only FDA approved treatment for Pompe disease, however, gene therapy with naturally occurring and engineered adeno-associated viral vectors are also widely studied as an alternative treatment. In the present study we directly compared the benefits of existing and novel treatment modalities - ERT, AAV9-GAA, and AAVcc47-GAA, with an emphasis on correction of pathologies related to respiratory function. We find that GAA replacement in early adult mice improves respiration through 9 months of age. This improvement is attributed to glycogen clearance in the tongue, diaphragm, and lungs, which subsequently improved diaphragm neuromuscular junctions and reduced lysosomes within the alveolar epithelia.