Résumé :
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Duchenne muscular dystrophy, the most common and serious form of childhood muscle wasting, is one of the greatest challenges for cell/gene therapies, due to the widespread and complex nature of dystrophin gene expression. Antisense oligomers can interfere with exon recognition and pre-mRNA processing, thereby targeting specific exons for exclusion from the mature mRNA, thus exons carrying protein-truncating mutations can be removed, or exons flanking frame-shifting genomic deletions may be skipped to restore the mRNA reading frame. Molecular characterization of mildly affected Becker MD patients indicate substantial portions of the dystrophin gene transcript/protein can be lost with minimal functional consequences. One clinical trial to assess safety and confirm proof-of-principle of exon skipping after localized administration of an oligomer into human dystrophic muscle has been completed in the Netherlands, and another compound is currently being evaluated in the United Kingdom. Efficient systemic oligomer delivery must be achieved before therapeutic benefits are likely to be observed, and different dystrophin mutations will require distinct therapeutic exon skipping compounds and strategies. A handful of oligomers may restore the reading-frame in most genomic deletions, but many more compounds will be needed to by-pass small protein-truncating mutations spread across the gene. Targeted exon skipping to treat DMD must become recognized as a personal genetic therapy, if therapeutic benefits are to be induced in potentially responsive DMD patients with different dystrophin gene lesions. This will require fundamental shifts on how drugs are recognized and regulated, especially for small patient populations, sometimes limited to one individual. However, success with DMD exon skipping may open therapeutic opportunities for other neuromuscular disorders, which may arise from either selected splice mutations (15% of all gene mutations alter splicing patterns), abnormal splicing arising from triplet repeat expansions (Myotonic Dystrophy Type I) or inappropriate splicing of the SMN2 gene trancript (SMA).
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