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

Absence of functional acid--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 post-natal day 1; rats were studied at 6-12 months old. Whole-body plethysmography showed that reduced inspiratory tidal volumes in Gaa-/-rats were corrected by AAV-GAA treatment. Matrix- assisted laser desorption/ionization mass spectrometry imaging (MALDI) revealed that AAV-GAA treatment normalized diaphragm muscle glycogen as well as glycans. Neurophysiological recordings of phrenic nerve output and immunohistochemical evaluation of the cervical spinal cord indicated a neurologic benefit of AAV-GAA treatment. 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. 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.