Abstract
Exon skipping using antisense oligonucleotides represents a
potential effective disease modifying treatment in Duchenne
muscular dystrophy (DMD). However there is debate regarding
the functional properties of the internally deleted dystrophins
produced by exon skipping and whether the skipping of some
exons is more beneficial than others. In order to better predict the
outcome of exon skipping clinical trials we have characterised the
clinical phenotype of 17 Becker muscular dystrophy (BMD) patients
harbouring in-frame deletions relevant to on-going or planned exon
skipping clinical trials for DMD and correlated it to the levels of
dystrophin, and dystrophin-associated protein expression. Patients
were selected exclusively on the basis of their genotype; all were
classified clinically as BMD and were grouped into asymptomatic
(4 patients), mild (12 patients) and severe (1 patient) categories.
All 17 patients had dystrophin levels of at least 40% of control with
the asymptomatic group having significantly higher dystrophin
(p = 0.013), b-dystroglycan (p = 0.025) and neuronal nitric oxide
synthase (nNOS, p = 0.034) expression compared with symptomatic
BMD patients. Furthermore, patients with deletions ending in
exon 51 (whose skipping could rescue the largest group of DMD
deletions) showed significantly higher dystrophin levels (p = 0.034)
than those with deletions ending with exon 53. This is the first
quantitative study on both dystrophin and dystrophin-associated
protein expression in BMD patients with deletions relevant for ongoing and future DMD exon skipping clinical trials. Taken together
our results indicate that a significant clinical benefit from the
production the internally deleted dystrophins assessed in this study
is a realistic possibility.
potential effective disease modifying treatment in Duchenne
muscular dystrophy (DMD). However there is debate regarding
the functional properties of the internally deleted dystrophins
produced by exon skipping and whether the skipping of some
exons is more beneficial than others. In order to better predict the
outcome of exon skipping clinical trials we have characterised the
clinical phenotype of 17 Becker muscular dystrophy (BMD) patients
harbouring in-frame deletions relevant to on-going or planned exon
skipping clinical trials for DMD and correlated it to the levels of
dystrophin, and dystrophin-associated protein expression. Patients
were selected exclusively on the basis of their genotype; all were
classified clinically as BMD and were grouped into asymptomatic
(4 patients), mild (12 patients) and severe (1 patient) categories.
All 17 patients had dystrophin levels of at least 40% of control with
the asymptomatic group having significantly higher dystrophin
(p = 0.013), b-dystroglycan (p = 0.025) and neuronal nitric oxide
synthase (nNOS, p = 0.034) expression compared with symptomatic
BMD patients. Furthermore, patients with deletions ending in
exon 51 (whose skipping could rescue the largest group of DMD
deletions) showed significantly higher dystrophin levels (p = 0.034)
than those with deletions ending with exon 53. This is the first
quantitative study on both dystrophin and dystrophin-associated
protein expression in BMD patients with deletions relevant for ongoing and future DMD exon skipping clinical trials. Taken together
our results indicate that a significant clinical benefit from the
production the internally deleted dystrophins assessed in this study
is a realistic possibility.
| Original language | English |
|---|---|
| Journal | Neuromuscular Disorders |
| Publication status | Published - 2012 |