1. Neonatal systemic gene therapy restores cardiorespiratory function in a rat model of Pompe disease.
- Author
-
Fuller DD, Rana S, Thakre P, Benevides E, Pope M, Todd AG, Jensen VN, Vaught L, Cloutier D, Ribas RA, Larson RC, Gentry MS, Sun RC, Chandran V, Corti M, Falk DJ, and Byrne BJ
- Abstract
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 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., Competing Interests: R.C.S. is a member of the Medical Advisory Board for Little Warrior Foundation. M.S.G. has research support and research compounds from Maze Therapeutics, Valerion Therapeutics, Ionis Pharmaceuticals. M.S.G. also received consultancy fee from Maze Therapeutics, PTC Therapeutics, and the Glut1-Deficiency Syndrome Foundation. BJB has received research support from Sarepta Therapeutics, Amicus Therapeutics and is a member of the Global Pompe Advisory Board supported by Sanofi. BJB has received consulting fees from Amicus Therapeutics, Rocket Pharma, Pfizer, and Tenaya. MC and BJB are co-founders of and Ventura Life Sciences, LLC. BJB is an uncompensated member of the MDA Board or Directors.MC has received research support from the Friedreich’s Ataxia Research Alliance. MC and BJB are co-founders of and Ventura Life Sciences, LLC. The University of Florida is entitled to licensing revenue related to Pompe disease inventions. The remaining authors declare no competing interests.- Published
- 2024
- Full Text
- View/download PDF