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.
Keywords: Exon-skipping, exon re-inclusion, gene therapy, neuromuscular disorders, small nuclear RNA, splicing modulation,
viral vectors, U7, DMD, CAG
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