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

Pompe disease (PD) is a neuromuscular disorder caused by deficiency of acid-alpha-glucosidase (GAA), leading to motor and respiratory dysfunctions. Available Gaa knock-out (KO) mouse models do not accurately mimic PD, particularly the highly impaired respiratory phenotype. Methods. Here we developed a new mouse model of PD crossing Gaa KO B6;129 with DBA2/J mice. Findings. Male Gaa KODBA2/J presents most of the key features of the human disease, including early lethality, severe respiratory impairment, cardiac hypertrophy and muscle weakness. Transcriptome analyses of Gaa KODBA2/J, compared to the parental Gaa KOB6;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 in Gaa KODBA2/J, were significantly improved upon gene therapy with AAV vectors expressing a secreted GAA enzyme. Transcriptomic analysis comparing the gene expression profiles of quadriceps muscle and whole spinal cord from: Gaa WT and Gaa KO mice in B6;129 background; Gaa WT and Gaa KO mice in B6;129;DBA2/J background and Gaa KO mice in B6;129;DBA2/J strain treated with AAV-mediated gene therapy with secreted acid-alpha-glucosidase.