P.148Long-term natural history data in Duchenne muscular dystrophy ambulant patients with mutations amenable to skip exons 44, 45, 51 and 53

Abstract

Recent clinical trials using dystrophin restoration approaches, such as antisense oligonucleotides for exons skipping or approaches targeting non-sense mutations have shown encouraging results. The interpretation of the long-term results of the clinical trials however is complicated by the paucity of long-term prospective natural history data in patients with distinct genotypes. Retrospective data on loss of ambulation and other features of disease progression in patients with deletions amenable to skip exon 44, 45, 51 and 53 have reported prospectively collected longitudinal data suggesting that the changes in the individual subgroups becomes to be more evident on a longer follow up (24 months). As there are a number of ongoing or planned studies targeting deletions amenable to skip exon 44, 45, 51 and 53 it has become important to obtain more detailed information on the patterns of progression related to different genotypes. The aim of this international collaborative effort was to obtain longitudinal changes over 36 months in the six minutes walking test (6MWT) in a large cohort of DMD ambulant patients amenable to skip exons 44, 45, 51 and 53. Of the 92 patients included in the study, 24 had deletions amenable to skip exon 44, 27 exon 45, 18 exon 51, and 28 exon 53. Five patients with a single deletion of exon 52 were counted in both subgroups skipping exon 51 and 53. The difference between subgroups amenable to skip different exons was not significant at 12 months but became significant at both 24 (p<0.05) and 36 months (p<0.01). Mutations amenable to skip exon 53 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had better results both at baseline and at follow up. Deletions amenable to skip exon 45 were associated with a more variable pattern of progression. Single exon deletions were more often associated with less drastic changes but this was not always true in individual cases. Our results confirm that the progression of disease can differ between patients with different deletions, although the changes only become significant from 24 months onwards. This information is relevant because there are current clinical trials specifically targeting patients with these subgroups of mutations.