26 | Validation of a new multi-target antioxidant treatment for the therapy of Duchenne muscular dystrophy

F. Fontana^1|2, F. Carozzi¹, G. Piccoli³, L. Nogara³, G. Romagnoli², E. Petricci², B. Blaauw³, M. Canton³, Libero Vitiello¹, F. Galvagni² | ¹Dept. of Biology, Univ. of Padova, Italy; ²Dept. of Biotechnology, Chemistry and Pharmacy, Univ. of Siena, Italy; ³Dept. of Biomedical Sciences, Univ. of Padova, Italy.

Currently, there is no general cure for Duchenne muscular dystrophy (DMD); standard therapy with corticosteroids only slows the progression of the disease, while often causing significant side effects. Therefore, there is a clear need for new, mutation-independent effective therapeutics with favourable side effect profiles. In DMD, dystrophin deficiency triggers a series of pathophysiological events, e.g., calcium dysregulation, mitochondrial disfunction, oxidative stress, inflammatory and immune responses, and impaired muscle regeneration. Experimental therapies in the past usually focused on only one of these aspects at the time, limiting the efficacy of these approaches. A therapeutic strategy capable of simultaneously acting on multiple DMD pathophysiological features would therefore be highly desirable. To this aim, we identified the key transcriptional regulator NRF2 as a promising pharmacological target, which can be specifically activated by the small molecule Nacetylcysteine ethyl ester (NACET). Here we report the initial results obtained by treating young mdx mice with NACET from 6 to 10 weeks of age. So far, we found that the highest dosage led to a significant improvement of normalized force in hindlimb muscles and to a decrease in the percentage of necrotic fibers, in the absence of any adverse side effects.