Therapeutic exon skipping for dysferlinopathies?
Résumé
Antisense-mediated exon skipping is a promising therapeutic approach for Duchenne muscular dystrophy (DMD) currently tested in clinical trials. The aim is to reframe dystrophin transcripts using antisense oligonucleotides (AONs). These hide an exon from the splicing machinery to induce exon skipping, restoration of the reading frame and generation of internally deleted, but partially functional proteins. It thus relies on the characteristic of the dystrophin protein, which has essential N- and C- terminal domains, while the central rod domain is largely redundant. This approach may also be applicable to Limb Girdle Muscular Dystrophy type 2B (LGMD2B), Myoshi Myopathy (MM) and distal myopathy with anterior tibial onset (DMAT), which are caused by mutations in the dysferlin-encoding DYSF gene. Dysferlin has a function in repairing muscle membrane damage. Dysferlin contains calcium dependent C2 lipid binding (C2) domains and an essential transmembrane domain. However, mildly affected patients where one or a large number of DYSF exons were missing have been described, suggesting that internally deleted dysferlin proteins can be functional. Thus, exon skipping might also be applicable as a LGMD2B, MM and DMAT therapy. We have here analyzed the dysferlin protein domains and DYSF mutations and describe which exons are promising targets with regard to applicability and feasibility. We also show that DYSF exon skipping appears to be as straightforward as DMD exon skipping as AONs to induce efficient skipping of 4 DYSF exons were readily identified.
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