Comparison of the phenotypes of patients harboring in-frame deletions starting at exon 45 in the Duchenne muscular dystrophy gene indicates potential for the development of exon skipping therapy

Abstract

Exon skipping therapy has recently received attention for its ability to convert the phenotype of lethal Duchenne muscular dystrophy (DMD) to a more benign form, Becker muscular dystrophy (BMD), by correcting the open reading frame. This therapy has mainly focused on a hot-spot (exons 45-55) mutation in the DMD gene. Exon skipping of an entire stretch of exons 45-55 is an approach applicable to 46.9% of DMD patients. However, the resulting phenotype is not yet fully understood. Here we examined the clinical profiles of 24 patients with BMD resulting from deletions starting at exon 45. The Δ45-55 group ranged in age from 2 to 87 years; no mortality was observed, and one patient was ambulatory at 79 years of age. The age at which patients became wheelchair-bound in the Δ45-48 group (18-88 years old) was approximately 50 years. Cardiomyopathy was well controlled by pharmaceuticals in both deletion groups. In contrast, the Δ45-47 and Δ45-49 groups exhibited more severe phenotypes than those with other mutations: the age at which patients in the Δ45-49 group became wheelchair-bound was around 30-40 years. Our study shows that clinical severity differs between each hot-spot deletion.

Quantitative Antisense Screening and Optimization for Exon 51 Skipping in Duchenne Muscular Dystrophy

“…Additionally, the assessment of therapeutic outcomes from exon 51 skipping needs to be carefully considered because of differences in the functionality and stability of truncated proteins, arising from structural differences owing to variously skipped exons, as observed in BMD phenotypes with different in-frame mutations. 37,38 As revealed in the present study using mdx52 mice, effective AO sequences and/or target positions to skip a certain exon are different between species, which had not previously been demonstrated. This difference may be because of species specificity in how the splicing machinery works or in the dystrophin gene sequence itself.…”

Pharmacological inhibition of REV-ERB stimulates differentiation, inhibits turnover and reduces fibrosis in dystrophic muscle

“…More radical cell replacement therapies like autologous bone marrow transplant have not been comprehensively tested as clinically viable treatments 11 . Similarly inuitively appealing methods; exon skipping therapies, that attempt to rescue dystrophin protein expression in skeletal muscle (SkM) have been tested in patients 12 – 14 . These treatments utilize antisense oligonucleotides (AONs) to modify mRNA splicing of dystrophin transcripts and can potentially yield therapeutic benefits in about 83% of DMD patients.…”

Skipping Multiple Exons to Treat DMD—Promises and Challenges

“…Additionally, multi-exon skipping offers the prospect of selecting the truncated dystrophin that optimizes the protein function or stability. For example, DMD exons 3–9 deletion and exons 45–55 deletion are both known to be associated with a remarkably mild BMD phenotype compared to smaller in-frame deletions in these regions [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. The systemic effects of antisense-mediated multi-exon skipping tested in some of the models include: mdx52 mice with exon 52 deletion for multi-skipping of exons 45–55 [ 17 , 37 , 38 ] and canine X-linked muscular dystrophy (CXMD) dogs for multi-skipping of exons 6–9 [ 39 ].…”

“…Exons 3–9 and exons 45–55 are found to be mutational hotspots in the DMD gene, covering approximately 7% and 47% of patients, respectively [ 30 , 36 ]. According to a medical case study in 2016, a 27-year-old male exhibited an asymptomatic phenotype with a deletion of exons 3–9 [ 30 ].…”

“…Most of the patients with an in-frame mutation where exons 45–55 are skipped express a very mild BMD or asymptomatic phenotype [ 31 , 32 , 64 ]. Interestingly, exons 45–55 of the DMD gene cover the mutation hotspot [ 36 ]. Therefore, multi-exon skipping of exons 45–55 using AOs is a promising strategy that could treat almost 47% of DMD patients [ 36 ].…”