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.