Neonatal systemic gene therapy restores cardiorespiratory function in a rat model of Pompe disease.

Absence of functional acid-α-glucosidase (GAA) leads to early onset Pompe disease with cardiorespiratory and neuromuscular failure. A novel Pompe rat model (Gaa^-/-) was used to test the hypothesis that neonatal gene therapy with adeno-associated virus serotype 9 (AAV9) restores cardiorespiratory neuromuscular function across the lifespan. Temporal vein administration of AAV9-DES-GAA or sham (saline) injection was done on postnatal day 1; rats were studied at 6-12 months old. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI) revealed that AAV-GAA treatment normalized diaphragm muscle glycogen as well as glycans. In vivo magnetic resonance imaging demonstrated that impaired cardiac volumes in Gaa^-/- rats were corrected by AAV-GAA treatment. Biochemical assays showed that AAV treatment increased GAA activity in the heart, diaphragm, quadriceps, and spinal cord. Inspiratory tidal volume and minute ventilation were increased in AAV-GAA-treated vs. saline-treated Pompe rats. Neurophysiological phrenic nerve recordings and spinal histological evaluation indicated that AAV-GAA treatment drove functional neuronal GAA expression. We conclude that neonatal AAV9-DES-GAA therapy drives sustained, functional GAA expression and improved cardiorespiratory function in the Gaa^-/- rat model of Pompe disease.