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

David D Fuller¹, Sabhya Rana², Prajwal P Thakre², Ethan S Benevides³, Megan K Pope⁴, Adrian G Todd⁵, Victoria N Jensen⁶, Lauren Vaught⁴, Denise A Cloutier⁴, Roberto A Ribas⁷, Reece C Larson⁷, Matthew S Gentry⁷, Ramon C Sun⁸, Vijay Chandran⁴, Manuela Corti⁵, Darin J Falk⁵, Barry J Byrne⁵

Affiliations

¹ Department of Physical Therapy, University of Florida, Gainesville, FL, USA; Breathing Research and Therapeutics Center, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA. Electronic address: ddf@phhp.ufl.edu.
² Department of Physical Therapy, University of Florida, Gainesville, FL, USA; Breathing Research and Therapeutics Center, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
³ Breathing Research and Therapeutics Center, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Department of Pediatrics, University of Florida, Gainesville, FL, USA.
⁴ Department of Pediatrics, University of Florida, Gainesville, FL, USA.
⁵ Department of Pediatrics, University of Florida, Gainesville, FL, USA; Powell Gene Therapy Center, University of Florida, Gainesville, FL, USA.
⁶ Department of Physical Therapy, University of Florida, Gainesville, FL, USA.
⁷ Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA.
⁸ McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA.

PMID: 40518673
PMCID: PMC12432874 (available on 2026-09-03)
DOI: 10.1016/j.ymthe.2025.06.022

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

David D Fuller et al. Mol Ther. 2025.

. 2025 Sep 3;33(9):4276-4289.

doi: 10.1016/j.ymthe.2025.06.022. Epub 2025 Jun 14.

Authors

Affiliations

¹ Department of Physical Therapy, University of Florida, Gainesville, FL, USA; Breathing Research and Therapeutics Center, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA. Electronic address: ddf@phhp.ufl.edu.
² Department of Physical Therapy, University of Florida, Gainesville, FL, USA; Breathing Research and Therapeutics Center, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
³ Breathing Research and Therapeutics Center, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Department of Pediatrics, University of Florida, Gainesville, FL, USA.
⁴ Department of Pediatrics, University of Florida, Gainesville, FL, USA.
⁵ Department of Pediatrics, University of Florida, Gainesville, FL, USA; Powell Gene Therapy Center, University of Florida, Gainesville, FL, USA.
⁶ Department of Physical Therapy, University of Florida, Gainesville, FL, USA.
⁷ Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA.
⁸ McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA.

PMID: 40518673
PMCID: PMC12432874 (available on 2026-09-03)
DOI: 10.1016/j.ymthe.2025.06.022

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 postnatal day 1; rats were studied at 6-12 months old. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI) revealed that AAV-GAA treatment normalized diaphragm muscle glycogen as well as glycans. 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. Inspiratory tidal volume and minute ventilation were increased in AAV-GAA-treated vs. saline-treated Pompe rats. Neurophysiological phrenic nerve recordings and spinal histological evaluation indicated that AAV-GAA treatment drove functional neuronal GAA expression. 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.

Keywords: AAV; Pompe; diaphragm; neonatal; respiratory; spinal.

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Conflict of interest statement

Declaration of 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. B.J.B. has received research support from Sarepta Therapeutics, Amicus Therapeutics, and is a member of the Global Pompe Advisory Board supported by Sanofi. B.J.B. has received consultancy fee from Amicus Therapeutics, Rocket Pharma, Pfizer, and Tenaya. M.C. and B.J.B. are co-founders of Ventura Life Sciences, LLC. B.J.B. is an uncompensated member of the MDA Board or Directors. M.C. has received research support from the Friedreich’s Ataxia Research Alliance. M.C. and B.J.B. are co-founders of Ventura Life Sciences, LLC. The University of Florida is entitled to licensing revenue related to Pompe disease inventions.

Update of

Neonatal systemic gene therapy restores cardiorespiratory function in a rat model of Pompe disease.
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, Byrne BJ. Fuller DD, et al. bioRxiv [Preprint]. 2024 Dec 16:2024.12.10.627800. doi: 10.1101/2024.12.10.627800. bioRxiv. 2024. Update in: Mol Ther. 2025 Sep 3;33(9):4276-4289. doi: 10.1016/j.ymthe.2025.06.022. PMID: 39763722 Free PMC article. Updated. Preprint.

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

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

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

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LinkOut - more resources

Full Text Sources

Medical

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