Rachid Benchaouir and Aurelie Goyenvalle Pages 179 - 191 ( 13 )
Splice-modulation therapy aiming at correcting genetic defects by molecular manipulation of the premessenger RNA is a promising novel therapeutic approach for genetic diseases. In recent years, these new RNA based strategies, mostly mediated by antisense oligonucleotides (AO), have demonstrated encouraging results for muscular dystrophies, a heterogeneous group of genetic disorders characterized by muscle weakness and wasting. In particular, the clinical evaluation of antisense-mediated exon-skipping for the treatment of Duchenne muscular dystrophy has shown convincing data and therefore raised hopes and expectations for neuromuscular disorders therapy. However, AO-mediated splicing modulation still faces major hurdles such as low efficacy in specific tissues, poor cellular uptake and relatively rapid clearance from circulation, which means repeated administrations are required to achieve some therapeutic efficacy. To overcome these limitations, small nuclear RNAs (snRNA) have been used to shuttle the antisense sequences, offering the advantage of a correct subcellular localization with pre-mRNAs and the potential of a permanent correction when introduced into viral vectors. Here we review the recent progress in the development of snRNA mediated splicing modulation for muscular dystrophies, focusing on the advantages offered by this technology over classical AOs but also the challenges limiting their clinical application.
Exon-skipping, exon re-inclusion, gene therapy, neuromuscular disorders, small nuclear RNA, splicing modulation, viral vectors, U7, DMD, CAG
Equipe Biotherapies des Maladies Neuromusculaires, Unite Mixte : Um76 UPMC - UMR 7215 CNRS - U974 Inserm - Institut de Myologie, Faculte de Medecine Pierre et Marie Curie, 105 Boulevard de l'hopital, 75013 Paris, France.