Echigoya Y, Lim KRQ, Nakamura A, Yokota T. Multiple Exon Skipping in the Duchenne Muscular Dystrophy Hot Spots: Prospects and Challenges. Journal of personalized medicine 2018;8
At the moment exon skipping is tested for several exons. These compounds, however, induce the skipping of a single exons. Not all patients are eligible for single exon skipping. Some require the skipping of multiple exons. Multiple exon skipping is even more challenging than single exon skipping, since all exons have to be skipped in order to be successful. Another argument for multiple exon skipping could be that one therapy would be applicable to a larger group of patients (all compounds for skipping single exons have to be tested individually). This review discusses the current (2018) state-of-the art of multiple exon skipping.
Duchenne muscular dystrophy (DMD), a fatal X-linked recessive disorder, is caused mostly by frame-disrupting, out-of-frame deletions in the dystrophin (DMD) gene. Antisense oligonucleotide-mediated exon skipping is a promising therapy for DMD. Exon skipping aims to convert out-of-frame mRNA to in-frame mRNA and induce the production of internally-deleted dystrophin as seen in the less severe Becker muscular dystrophy. Currently, multiple exon skipping has gained special interest as a new therapeutic modality for this approach. Previous retrospective database studies represented a potential therapeutic application of multiple exon skipping. Since then, public DMD databases have become more useful with an increase in patient registration and advances in molecular diagnosis. Here, we provide an update on DMD genotype-phenotype associations using a global DMD database and further provide the rationale for multiple exon skipping development, particularly for exons 45(-)55 skipping and an emerging therapeutic concept, exons 3(-)9 skipping. Importantly, this review highlights the potential of multiple exon skipping for enabling the production of functionally-corrected dystrophin and for treating symptomatic patients not only with out-of-frame deletions but also those with in-frame deletions. We will also discuss prospects and challenges in multiple exon skipping therapy, referring to recent progress in antisense chemistry and design, as well as disease models.