AAV9 gene therapy to target respiratory insufficiency in the D2.mdx mouse model of duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by a deficiency of dystrophin. Dystrophin deficiency leads to progressive muscle weakness, including involvement of the respiratory muscles, ultimately resulting in respiratory failure. Adeno-associated virus (AAV)-mediated gene therapy carrying a microdystrophin (µDys) transgene was recently approved by the Food and Drug Administration (FDA); however, its effects on the respiratory system remain unclear. Further, effective transduction of all muscle groups requires high systemic AAV doses, which are associated with dose-dependent toxicities. In this study, we investigated whether respiratory-directed gene therapy can 1) specifically target respiratory muscles and (2) reduce the total AAV-µDys dose required for therapeutic benefit. We compared the efficiency of AAV9-µDys delivery using different administration routes and dosages in D2.mdx mice, a mouse model of DMD. AAV9-µDys was administered either systemically at a high dose, locally at intermediate doses via intralingual and intrathoracic injections, or through a combination of systemic and respiratory-directed intermediate dosing. All treatments resulted in improved respiratory muscle dystrophin expression and decreased pathology; however, the intermediate and combination dosing led to lower liver vector genome expression. In conclusion, respiratory-targeted gene therapy can improve respiratory muscle pathology while reducing the need for high systemic AAV doses associated with liver toxicity.

Duke Scholars

Author Debolina Biswas  

Author Mai ElMallah Pediatrics, Pulmonary and Sleep Medicine