Enhancing antisense oligonucleotide efficacy in Duchenne muscular dystrophy by histone deacetylase inhibitors drug repurposing

Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disease caused by mutations, especially deletions, in the DMD gene. The mutations lead to a reduction of mature transcript levels and an impairment of expression throughout its length (transcript imbalance), in DMD patients. Recently, it was proposed that epigenetic changes in the DMD locus could be responsible for these phenomena. The amount and stability of the DMD transcript are critical factors for genetic therapies that target premRNA, such as antisense oligonucleotides (AONs) that show efficient exon removal but limited protein restoration, both in clinical and in-vitro studies. Here, we want to use histone deacetylase enzymes (HDACi) to facilitate the DMD-locus transcription, in order to enhance the ASOs biological target and consequently the level of restored protein. We will test only approved drugs in order to facilitate the translation into clinic of this proposal. Positive results would have a great impact on all the DMD patients treatable with AONs, which comprise, at the moment, 30% of the DMD population but this number will increase as new ASOs enter the clinical landscape.