Epigenetic drugs as a pharmacological approach in Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is the most severe form of dystrophy that leads to progressive muscle weakness because of a gradual replacement of functional muscle with fat and fibrotic scars. Pharmacological therapies for DMD should therefore aim to counteract this fibro-adipogenic degeneration and to promote the compensatory regeneration to slow down progression of pathology. Previous works proved pre-clinical efficacy of pan-histone deacetylase inhibitors (HDACi) in the treatment of murine models of DMD, showing the ability of HDACi to counter disease progression and to induce functional and morphological recovery. These studies paved the way for ongoing clinical trials on dystrophic boys but the use of pan- HDACi raises several concerns because of their lack of selectivity and the potential to induce adverse effects over longer period of treatment. Thus, an urgency in the field of epigenetic pharmacology is to develop more selective strategies. Other epigenetic modifiers, such as Histone Lysine Methyltransferases (KMTs) are emerging as particularly relevant in myogenesis. In particular, Histone 3 Lysine 9 (H3K9) KMTs are implicated in the dynamic control of gene expression in myogenic precursors and are highly specific for their targets. Therefore, the development of KMTs specific inhibitors might be a strategy to increase selectivity of epigenetic therapies. We aimed here to test pre-clinical efficacy of newly developed specific inhibitors for class I HDACs (I-HDACi) and H3K9 KMTs (KMTi) in murine models of skeletal muscle regeneration and DMD. We reason that modulation of these epigenetic modifiers could represent a way to promote the expression of muscle-specific genes and to enhance muscle differentiation in cells or tissues whose myogenic capacity is compromised, such as DMD. In agreement with this idea, we show here that the in vivo inhibition of H3K9 KMTs and class I HDACs efficiently promotes an overall muscle regeneration in injured wild type mice and mdx mice (the murine model for DMD). These drugs promote an increasement of myofibers’ size, and reduction of adipogenic, fibrotic and inflammatory infiltrations. Our data indicate that the pharmacological treatment with these specific epigenetic drugs might become an effective therapeutic approach to counteract the degeneration in DMD. The results of these studies will provide important insights to further develop these drugs and even to conceive future combined therapies targeting both HDACs and KMTs.