Correcting Neuromuscular Deficits With Gene Therapy in Pompe Disease

Objective We have recently reported on the pathology of the neuromuscular junction (NMJ) in Pompe disease, reflecting disruption of neuronal and muscle homeostasis as a result of glycogen accumulation. The aim of this study was to examine how the alteration of NMJ physiology contributes to Pompe disease pathology; we performed molecular, physiological, and histochemical analyses of NMJ‐related measures of the tibialis anterior muscles of young‐, mid‐, and late‐stage alpha‐glucosidase (GAA)‐deficient mice. Methods We performed intramuscular injection of an adeno‐associated virus (AAV)9 vector expressing GAA (AAV9‐hGAA) into the tibialis anterior muscle of Gaa–/– mice at early, mid, and severe pathological time points. We analyzed expression of NMJ‐related genes, in situ muscle force production, and clearance of glycogen in conjunction with histological assessment of the NMJ. Results Our data demonstrate that AAV9‐hGAA is able to replace GAA to the affected tissue and modify AChR mRNA expression, muscle force production, motor endplate area, and innervation status. Importantly, the degree of restoration for these outcomes is limited by severity of disease. Early restoration of GAA activity was most effective, whereas late correction of GAA expression was not effective in modifying parameters reflecting NMJ structure and function nor in force restoration despite resolution of glycogen storage in muscle. Interpretation Our data provide new mechanistic insight into the pathology of Pompe disease and suggest that early systemic correction to both neural and muscle tissues may be essential for successful correction of neuromuscular function in Pompe disease. Ann Neurol 2015;78:222–234