Ricerc@Sapienza

Duchenne Muscular Dystrophy (DMD) is one of the most severe neuromuscular diseases, affecting 1:3500 males born alive. It is a monogenic disorder caused by mutations in the largest human gene, the one encoding for the dystrophin protein. The lack of the protein affects the activity of skeletal muscles as well as that of heart and diaphragm leading the patients to the wheel chair by the age of 13 and to death by the third decade of age. The proposed project should possibly lead to the identification of therapeutic compounds for the DMD cases in which the open reading frame of dystrophin would be restored by exon 45 skipping; such cases represent almost 10% of the entire DMD population. The project is based on a recently identified DMD patient that, even if carrying a typical Duchenne mutation (exon 44 deletion), displays a Becker-like phenotype thanks to natural exon 45 skipping. The case reported is a 21 years-old boy that can walk and breath autonomously, but is unable to stand up from the ground. We have described (Martone et al. 2016, Nat. Commun. 7:10488) that in this patient, the absence of a specific splicing factor isoform (Celf2a) is able to cause the restoration of a dystrophin in-frame transcript, corresponding to 7% of total dystrophin amount, through endogenous skipping of exon 45. We demonstrated that Celf2a is needed for exon 45 inclusion in the dystrophin transcript. These data suggested that drug dependent inhibition of this factor, that could be applicable to almost 7.000 DMD-affected people in Europe and to 100.000 at a worldwide scale, could become a powerful new therapeutic approach.
The aims of this project will be the finding of a small molecule able to inhibit Celf2a activity and the understanding of the molecular regulation of Celf2a expression.