Gene Therapy: Strategies to Treat Motor Unit Dysfunction.

Pompe disease results from a defi ciency or absence of the lysosomal enzyme acid alpha glucosidase (GAA), resulting in lysosomal glycogen accumulation that impacts cardiac, respiratory and neuromuscular function. Respiratory failure is the leading cause of morbidity and mortality in Pompe patients. AAV vectors expressing GAA are currently being evaluated in a phase I/II study in ventilator-dependent pediatric Pompe patients. These studies are based on the fi nding that accumulation of glycogen in spinal motor neurons contributes to weakness observed in Pompe disease. In a number of preclinical studies we have found that restoration of GAA activity in muscle and neural tissue is able to reverse ventilatory insuffi ciency by reversing motor neuron dysfunction. The principle defect in motor unit function is related to defi ciency in formation of the neuromuscular junction. New evidence also indicates the need for early intervention related to neural dysfunction since motor neurons show evidence of apoptosis in the murine model of Pompe. These defi cits are Gene Therapy: Strategies to Treat Motor Unit Dysfunction