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Review

Repair of pre-mRNA splicing: Prospects for a therapy for spinal muscular atrophy

Rachel Nlend Nlend, Kathrin Meyer and Daniel Schumperli

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Recent analyses of complete genomes have revealed that alternative splicing became more prevalent and important during eukaryotic evolution. Alternative splicing augments the protein repertoire - particularly that of the human genome - and plays an important role in the development and function of differentiated cell types. However, splicing is also extremely vulnerable, and defects in the proper recognition of splicing signals can give rise to a variety of diseases. In this review, we discuss splicing correction therapies, by using the inherited disease Spinal Muscular Atrophy (SMA) as an example. This lethal early childhood disorder is caused by deletions or other severe mutations of SMN1, a gene coding for the essential survival of motoneurons protein. A second gene copy present in humans and few non-human primates, SMN2, can only partly compensate for the defect because of a single nucleotide change in exon 7 that causes this exon to be skipped in the majority of mRNAs. Thus SMN2 is a prime therapeutic target for SMA. In recent years, several strategies based on small molecule drugs, antisense oligonucleotides or in vivo expressed RNAs have been developed that allow a correction of SMN2 splicing. For some of these, a therapeutic benefit has been demonstrated in mouse models for SMA. This means that clinical trials of such splicing therapies for SMA may become possible in the near future.

Authors

Rachel Nlend Nlend

Institute of Cell Biology, University of Bern, Switzerland

Kathrin Meyer

Institute of Cell Biology, University of Bern, Switzerland

Daniel Schumperli Corresponding author: daniel.schuemperli@izb.unibe.ch

Institute of Cell Biology, University of Bern, Switzerland

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.