Characterization of the phenotypic diversity in DupEx2 Duchenne Muscular Dystrophy and identification of predictive/prognostic markers

  • 2.9 Years 2022/2025
  • 193.600€ Total Award

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive weakening of skeletal muscles leading to loss of ambulation between 10-14 years. DMD is caused by mutations in the dystrophin gene and in 11% of these are duplications. The most promising therapeutic approaches include mutation-specific therapies. Notably, there is increasing evidence that specific groups of mutations may underlie different disease trajectories compared to the “average” DMD population. It is therefore mandatory to obtain more information about genotype-phenotype correlations and patterns of progression related to different genotypes.

Duplication of exon 2 (Dup2) is the most common DMD duplication and the only one for which a Phase I/IIa study on AAV-delivered, snRNA-mediated exon skipping is currently ongoing. Dup2 is expected to induce a severe DMD phenotype, consistent with most case series and large databases available to date. However, Dup2 has been occasionally reported with milder phenotype. We have identified all the viable Dup2 DMD patients in Italy: 26 subjects from 13 centers. Preliminary findings suggest that these patients have collectively a milder progression of the disease when compared to the classical DMD phenotype. More interestingly, about 30% of Dup2 patients have a significantly very milder phenotype, some of them still ambulatory at age of 20 years. Preliminary attempts to reveal mechanism involved in attenuating the phenotype seem to confute the hypothesis of alternative spicing transcripts as previously described for DMD patients harbouring deletion of exon 2. With the present application we propose to clinically characterize the Italian Dup2 population, including motor deterioration, respiratory and cardiac function, to perform whole genome sequencing to characterize DNA breakpoints to correlate with the phenotype and to collect available muscle biopsy samples and uro-stem cells/PBMC for future proteomic studies.

Scientific Publications

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