P.20.14 Non ambulant patients with deletion treatable by exon skipping 53 present a more severe phenotype than the general Duchenne population

Abstract

Exon skipping therapy is an emerging approach in Duchenne Muscular Dystrophy (DMD). Antisense oligonucleotides that skip exon 51, 44, 45, and 53 are currently evaluated in clinical trials. Knowing the precise phenotype of potentially eligible patients is important for designing the clinical trials. It is generally believed that there are few if any phenotypic differences between these different groups of patients or between these patients and the general DMD population. In preparation of exon 53 skipping mediated by an AAV8 construct, we recruited 24 patients aged from 6 to 20 years in an observational study of upper limb strength and function, using the Motor Function Measure (MFM), the Myogrip, the MyoPinch and the MoviPlate, three tools already validated in a large non ambulant DMD population. Data of 14 non ambulant DMD patients (13.8 ± 2.7 years) at inclusion were compared with 14 age and size-matched DMD controls (13.7 ± 2.6 years) with all types of mutation. DMD 53 patients scored significantly lower in the MFM (D3: 66 ± 17% vs. 82 ± 13% for DMD 53 vs. DMD control), had significant lower handgrip and key pinch strength on both hands. They had lost ambulation 13 months earlier (Age: 105 ± 20 vs. 118 ± 19 p = 0.04 for DMD 53 vs. DMD control). In order to rule out that this is due to a selection bias, we compared DMD 53 patients with other DMD patients carrying a deletion not involving the 45–55 region and looked at DMD patient cohort identified at the Cochin hospital’s routine diagnostic laboratory. We found that 91 DMD ex53 patients had lost ambulation at 108 ± 15 months, whilst other 400 non 45–55 DMD patients with a deletion had lost ambulation at 139 ± 54 months. Taken together, these preliminary data demonstrate that non-ambulant patients treatable by exon 53 skipping present a more severe phenotype than the general DMD population. This must be taken into account in the design of studies concerning this population.