Novel Exon-Skipping Therapeutic Approach for the DMD Gene Based on Asymptomatic Deletions of Exon 49

Mario Abaji (1) , Svetlana Gorokhova (1) , Nathalie da Silva (1) , Tiffany Busa (1) , Maude Grelet (2) , Chantal Missirian (1) , Sabine Sigaudy (1) , Nicole Philip (1) , France Leturcq (3) , Nicolas Levy (1) , Martin Krahn (1, 4) , Marc Bartoli (1)

1 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
2 Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse
3 CIC 1417 - CIC Cochin Pasteur
4 Département de génétique médicale [Hôpital de la Timone - APHM]

Exon skipping is a promising therapeutic approach. One important condition for this approach is that the exon-skipped form of the gene can at least partially perform the required function and lead to improvement of the phenotype. It is therefore critical to identify the exons that can be skipped without a significant deleterious effect on the protein function. Pathogenic variants in the DMD gene are responsible for Duchenne muscular dystrophy (DMD). We report for the first time a deletion of the in-frame exon 49 associated with a strikingly normal muscular phenotype. Based on this observation, and on previously known therapeutic approaches using exon skipping in DMD for other single exons, we aimed to extend the clinical use of exon skipping for patients carrying truncating mutations in exon 49. We first determined the precise genomic position of the exon 49 deletion in our patients. We then demonstrated the feasibility of skipping exon 49 using an in vitro AON (antisense oligonucleotide) approach in human myotubes carrying a truncating pathogenic variant as well as in healthy ones. This work is a proof of concept aiming to expand exon-skipping approaches for DMD exon 49.

Mots clés: genetics; pathological mechanisms; DMD; deletion; exon skipping; AON; muscular dystrophy; myopathy; therapy

Domaines: Génétique

Mario Abaji, Svetlana Gorokhova, Nathalie da Silva, Tiffany Busa, Maude Grelet, et al.. Novel Exon-Skipping Therapeutic Approach for the DMD Gene Based on Asymptomatic Deletions of Exon 49. Genes, 2022, 13 (7), ⟨10.3390/genes13071277⟩. ⟨hal-03780226⟩