AAV-μDys gene therapy to target respiratory deficits in the mdx mouse model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a devastating X-linked neuromuscular disorder caused by the absence of functional dystrophin, leading to progressive muscle degeneration, respiratory insufficiency, and ultimately cardiorespiratory failure. Adeno-associated viral (AAV) gene therapy carrying microdystrophin (μDys) was recently FDA approval for DMD, but its impact on respiratory function remains unclear. The goal of this study is to evaluate the therapeutic potential of AAV-cc47, an engineered AAV9-based capsid with enhanced cross-species transduction efficiency, delivering μDys in the mdx mouse model of DMD. The mice received systemic administration of AAV-cc47-μDys at 2mo of age and were assessed bi-monthly for respiratory function using whole-body plethysmography under normoxic (FiO : 0.21; N balance) and hypoxic–hypercapnic (FiCO : 0.07, FiO : 0.10; N balance) conditions, followed by terminal pulmonary mechanics evaluation via forced oscillation. Postmortem analyses were performed at 4mo and 12mo to assess short- and long-term treatment effects. The earlier time point showed no significant differences with therapy, however assessment at 12mo showed partial but significant enhancements in minute ventilation, peak inspiratory and expiratory flow along with overall pulmonary mechanics. Postmortem analysis showed ubiquitous distribution of vector genomes throughout the body, and an increase of dystrophin expression and decreased inflammation in the diaphragm of AAV-cc47-μDys-treated mdx mice. AAV-cc47-μDys treatment slightly improves respiratory function and muscle integrity but does not result in complete correction of DMD pathology. Funding: NHLBI R01HL171282 (MKE) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Duke Scholars

Author Aravind Asokan Surgery, Surgical Sciences