Non-Ambulant Duchenne Patients Theoretically Treatable by Exon 53 Skipping have Severe Phenotype

Abstract

Background: Exon skipping therapy is an emerging approach in Duchenne Muscular Dystrophy (DMD). Antisense oligonucleotides that induce skipping of exon 51, 44, 45, or 53 are currently being evaluated in clinical trials. These trials were designed on the basis of data available in general DMD population. Objectives: Our objective was to compare the clinical and functional statuses of non-ambulant DMD patients theoretically treatable by exon 53 skipping and of DMD patients with other mutations. Methods: We first compared fifteen non-ambulant DMD patients carrying deletions theoretically treatable by exon 53 skipping (DMD-53) with fifteen closely age-matched DMD patients with mutations not treatable by exon 53 skipping (DMD-all-non-53) then with fifteen DMD patients carrying deletions not treatable by exon 53 skipping (DMD-del-non-53). Results: We found that DMD-53 patients had a lower left ventricular ejection fraction, more contractures and they tend to have weaker grips and pinch strengths than other DMD patients. DMD-53 patients lost ambulation significantly younger than other DMD patients. This result was confirmed by comparing ages at loss of ambulation in all non-ambulant DMD patients of the DMD cohort identified in a molecular diagnostic lab.Conclusions: These prospective and retrospective data demonstrate that DMD-53 patients have clinically more severe phenotypes than other DMD patients.

Long-term natural history data in Duchenne muscular dystrophy ambulant patients with mutations amenable to skip exons 44, 45, 51 and 53

“…Retrospective data on loss of ambulation and other features of disease progression [5, 6] in patients with deletions amenable to skip exon 44, 45, 51 and 53 have recently become available, but only few have reported prospectively collected longitudinal data in these subgroups of patients[7–9]. These papers suggest that the changes in the individual subgroups do not appear to be significantly different from the mean changes observed in the whole cohort of DMD patients over a year [7], but the difference becomes more obvious on a longer follow up (24 months), especially when individual subgroups were compared to each other [8].…”

Longitudinal functional and NMR assessment of upper limbs in Duchenne muscular dystrophy

“…One limitation is potential generalization of such results to the overall DMD population. Although patients potentially treatable by exon 53 skipping tend to have more severe symptoms than the overall DMD population, 26 evolution over a 1-year period is similar to that of the general DMD population (data not shown). Several possible reasons could underlie the more severe phenotype of these patients: they may be smaller in stature compared to other patients with DMD, may have a smaller number of revertant fibers, and may have a weaker response to steroids.…”

DMD genotype correlations from the Duchenne Registry: Endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype

“…In the available data from the Duchenne Registry, we were able to retain a substantial number (N = 765) of males with an exonic duplication, nonsense mutation, or deletion mutation correctable by skipping exon 8, 44, 45, 50, 51, 52, 53, or 55 alongside their steroid usage and age at LOA. The availability of these multiple data types and the ability of participants to update data make the Duchenne Registry a robust data set for exploratory studies and natural history comparison because it is larger than all reported studies investigating DMD age at LOA combined (Bello et al, 2016;Pane et al, 2014;Servais et al, 2015;van den Bergen, et al, 2014). (Bello et al, 2016;van den Bergen et al, 2014).…”