Rescue of a severe mouse model for spinal muscular atrophy by U7 snRNA-mediated splicing modulation

K. Meyer, J. Marquis, J. Trub, R. Nlend Nlend, S. Verp, M-D. Ruepp, H. Imboden, I. Barde, D. Trono, D. Schumperli

Research output: Contribution to journalArticlepeer-review

87 Citations (Scopus)

Abstract

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 utilization of exon 7 and the production of functional protein. It has been hypothesized 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 germline 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.
Original languageEnglish
Pages (from-to)546-555
Number of pages10
JournalHuman Molecular Genetics
Volume18
Issue number3
DOIs
Publication statusPublished - 1 Feb 2009

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