T.P.26 Low dystrophin levels increase survival and improve pathology and motor function in dystrophin/utrophin double knockout mice

Abstract

Abstract In Duchenne Muscular Dystrophy (DMD) patients muscle fibers are susceptible to exercise-induced injury due to absence of functional dystrophin. No cure is available, but in the last decade major progress has been made in the challenge to restore dystrophin expression in DMD patients. It is unknown how much dystrophin is needed to slow or prevent disease progression. To elucidate this, we generated mdx-Xist Δhs utrn − / − mice in which skewed X-inactivation results in expression of variable, low dystrophin levels in a utrophin negative background. These mice ( n =20) underwent a 12week functional test regime after which histopathology was assessed. Dystrophin levels of 3–10% already significantly improved performance of two and four limb hanging wire tests and histopathology, while 10–17% further normalized this towards wild type. For improvement in grip strength higher dystrophin levels are needed. Most striking was the effect of already very modest dystrophin levels in maintenance of basic muscle function and protection against death from overall weakness. Whereas mdx/utrn − / − mice did not live beyond 12weeks, 62% of the mice expressing 3–10% dystrophin and all mice expressing 10–17% dystrophin survived 16weeks. A survival study in 42 mdx-Xist Δhs utrn − / − mice assessing skeletal muscle function and histopathology showed a median survival extension to 26weeks in mice with 3–10% dystrophin, while mice with 10–30% lived even longer. Biomarkers, skeletal muscle and heart function, and histopathology were significantly improved in mice with 3–10% dystrophin and further improvement was achieved with 10–30% dystrophin. These results suggest that even very low dystrophin levels already may have beneficial effects, and that survival and improvement of endurance efforts may be amongst the early effects of treatment. This underscores the urgency to develop better clinical readouts for the non-ambulatory phase.