DMD – Therapy

Kuntz, N.; Wagner, Kathryn R.; East, Lilly; Upadhyay, Sameer; Han, Baoqin; Koenig, E.; Steiner, Deborah; Shieh, Perry B.

doi:10.1016/j.nmd.2020.08.285

Cited by 4 publications

(1 citation statement)

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“…Among the exons we identified as associated with a significantly lower incidence of DMD, exon 45 is already being thoroughly studied as a target for the development of exon-skipping therapies [ 16 , 36 ]. Casimersen, an antisense drug of phosphorodiamidate morpholino chemistry to treat DMD amenable to exon 45 skipping, has recently been accepted and placed under priority review by the FDA [ 37 , 38 ]. The other five exons are also deemed promising therapeutic targets of exon skipping, although some of them are not applicable to many patients.…”

Section: Discussionmentioning

confidence: 99%

A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the DMD Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis

Anwar

Lim

et al. 2021

JPM

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Dystrophinopathies are caused by mutations in the DMD gene. Out-of-frame deletions represent most mutational events in severe Duchenne muscular dystrophy (DMD), while in-frame deletions typically lead to milder Becker muscular dystrophy (BMD). Antisense oligonucleotide-mediated exon skipping converts an out-of-frame transcript to an in-frame one, inducing a truncated but partially functional dystrophin protein. The reading frame rule, however, has many exceptions. We thus sought to simulate clinical outcomes of exon-skipping therapies for DMD exons from clinical data of exon skip-equivalent in-frame deletions, in which the expressed quasi-dystrophins are comparable to those resulting from exon-skipping therapies. We identified a total of 1298 unique patients with exon skip-equivalent mutations in patient registries and the existing literature. We classified them into skip-equivalent deletions of each exon and statistically compared the ratio of DMD/BMD and asymptomatic individuals across the DMD gene. Our analysis identified that five exons are associated with significantly milder phenotypes than all other exons when corresponding exon skip-equivalent in-frame deletion mutations occur. Most exon skip-equivalent in-frame deletions were associated with a significantly milder phenotype compared to corresponding exon skip-amenable out-of-frame mutations. This study indicates the importance of genotype-phenotype correlation studies in the rational design of exon-skipping therapies.

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Section: Discussionmentioning

confidence: 99%