Gene therapy with secreted acid alpha-glucosidase rescues Pompe disease in a novel mouse model with early-onset spinal cord and respiratory defects

BACKGROUND: Pompe disease (PD) is a neuromuscular disorder caused by deficiency of acidalpha-glucosidase (GAA), leading to motor and respiratory dysfunctions. Available Gaa knock-out (KO) mouse models do not accurately mimic PD, particularly its highly impaired respiratory phenotype. METHODS: Here we developed a new mouse model of PD crossing Gaa KO(B6;129) with DBA2/J mice. We subsequently treated Gaa KO(DBA2/J) mice with adeno-associated virus (AAV) vectors expressing a secretable form of GAA (secGAA). FINDINGS: Male Gaa KO(DBA2/J) mice present most of the key features of the human disease, including early lethality, severe respiratory impairment, cardiac hypertrophy and muscle weakness. Transcriptome analyses of Gaa KO(DBA2/J), compared to the parental Gaa KO(B6;129) mice, revealed a profoundly impaired gene signature in the spinal cord and a similarly deregulated gene expression in skeletal muscle. Muscle and spinal cord transcriptome changes, biochemical defects, respiratory and muscle function in the Gaa KO(DBA2/J) model were significantly improved upon gene therapy with AAV vectors expressing secGAA. INTERPRETATION: These data show that the genetic background impacts on the severity of respiratory function and neuroglial spinal cord defects in the Gaa KO mouse model of PD. Our findings have implications for PD prognosis and treatment, show novel molecular pathophysiology mechanisms of the disease and provide a unique model to study PD respiratory defects, which majorly affect patients. FUNDING: This work was supported by Genethon, the French Muscular Dystrophy Association (AFM), the European Commission (grant nos. 667751, 617432, and 797144), and Spark Therapeutics.