Delivery of cytoplasmic HDAC4 to treat DMD

This proposal aims to ameliorate the treatment currently in use for Duchenne Muscular Dystrophy (DMD) patients, by defining the potentiality of delivering Histone Deacetylase 4 (HDAC4) in skeletal muscle in a mouse model of DMD. The latter is a genetic, lethal pathology characterized by the progressive loss of skeletal muscle tissue, due to muscle fiber death combined with the decrease in the muscle’s ability to repair. Unfortunately, to date, there is no effective cure. We have recently studied HDAC4 in DMD, finding that in the cytoplasm it plays crucial protective functions in dystrophic muscles. Indeed, HDAC4 in the cytoplasm promotes both muscle repair and regeneration and its inhibition is deleterious for dystrophic muscles. These findings prompted us to study whether the delivery of the cytoplasmic form of HDAC4 is beneficial for muscular dystrophy in mice. Our new unpublished data clearly show that the delivery of cytoplasmic HDAC4 ameliorates dystrophic muscle architecture and function. Here, we propose to fully characterize the positive effects in terms of muscle fragility, repair, metabolism, and function, and to identify the signaling modulated by cytoplasmic HDAC4. Finally, we plan to deliver cytoplasmic HDAC4 by adenoviruses in dystrophic mice, to study the effects of its over-expression and to better mimic a clinical application. The final goal is to propose new therapeutic approaches for the treatment of Duchenne Muscular Dystrophy.