Gene therapy with secreted acid alpha-glucosidase rescues Pompe disease in a novel mouse model with early-onset spinal cord and respiratory defects
Pasqualina Colella, Pauline Sellier, Manuel J. Gómez, Maria Grazia Biferi, Guillaume Tanniou, Nicolas Guerchet, Mathilde Cohen-Tannoudji, Maryse Moya‐Nilges, Laetitia van Wittenberghe, Nathalie Danièle, Bernard Gjata, Jacomina Krijnse‐Locker, Fanny Collaud, Marcelo Simon‐Sola, Séverine Charles, Umut Cagin, Federico Mingozzi
Abstract
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: mice with adeno-associated virus (AAV) vectors expressing a secretable form of GAA (secGAA). FINDINGS: 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.