AAV-microutrophin gene therapy confers long-term cardioprotection against pharmacologic and exercise-induced injury in dystrophin deficiency.

Duchenne muscular dystrophy (DMD) is the most common childhood-onset muscle degenerative disease, caused by genetic deficiency of dystrophin, resulting in premature death due to cardiorespiratory failure. Gene therapy clinical trials employing adeno-associated virus (AAV) systemically delivering miniaturized dystrophin have provided mixed results with lingering concerns about safety, long-term efficacy, and the absence of information about cardiac protection. AAV-microutrophin (AAV-μUtro) represents an attractive alternative, previously shown in pre-clinical models to rescue skeletal muscle disease without stimulating an immune response to transgene product. It remains untested whether AAV-μUtro is protective in the dystrophic heart, in part due to limitations in DMD cardiomyopathy models. Here we present reproducible pharmacologic- and exercise-induced cardiac injury models in the mdx mouse and rigorous testing of AAV-μUtro for efficacy and durability. AAV-μUtro was highly protective against cardiac injury in these distinct models, evidenced by reduced cardiac troponin I levels and Evans Blue Dye uptake compared to untreated mdx mice. AAV-μUtro improved running performance following a cardiac stressor and prevented maladaptive cardiac remodeling in response to daily running 10 months-post-treatment. These results demonstrate AAV-μUtro's durable cardioprotection during cardiac stress and daily physical activity, and are promising with respect to meaningful amelioration of cardiac disease in children with DMD.