Human Molecular Genetics Advance Access published online on November 13, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn382
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Rescue of a severe mouse model for Spinal Muscular Atrophy by U7 snRNA-mediated splicing modulation
1 Institute of Cell Biology, University of Bern, Bern, Switzerland, EPFL Lausanne, Switzerland 2 Laboratory of Virology and Genetics, School of Life Sciences, EPFL Lausanne, Switzerland
* Correspondence to: Daniel Schümperli, Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland. E-mail: daniel.schuemperli{at}izb.unibe.ch, phone: +41 31 631 4675, fax: +41 31 631 4616.
Received October 9, 2008; Revised November 10, 2008; Accepted November 10, 2008
In Spinal Muscular Atrophy (SMA), the leading genetic cause of early childhood death, the survival motor neuron 1 gene (SMN1) is deleted or inactivated. The nearly identical SMN2 gene has a silent mutation that impairs the utilisation of exon 7 and the production of functional protein. It has been hypothesised that therapies boosting SMN2 exon 7 inclusion might prevent or cure SMA. Exon 7 inclusion can be stimulated in cell culture by oligonucleotides or intracellularly expressed RNAs, but evidence for an in vivo improvement of SMA symptoms is lacking. Here we unambiguously confirm the above hypothesis by showing that a bifunctional U7 snRNA that stimulates exon 7 inclusion, when introduced by germ-line transgenesis, can efficiently complement the most severe mouse SMA model. These results are significant for the development of a somatic SMA therapy, but may also provide new means to study pathophysiological aspects of this devastating disease.
3 Authors who contributed equally to this work and should be considered joint first authors
4 Present adress: Laboratory of Virology and Genetics, School of Life Sciences, EPFL Lausanne, Switzerland