title: Rescue of a severe mouse model for spinal muscular atrophy by U7 snRNA-mediated splicing modulation.
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.
authors.affiliation: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Meyer
authors.forename: Julien
authors.initials: J
authors.lastname: Marquis
authors.forename: Judith
authors.initials: J
authors.lastname: Trüb
authors.forename: Rachel
authors.initials: R
authors.lastname: Nlend Nlend
authors.forename: Sonia
authors.initials: S
authors.lastname: Verp
authors.forename: Marc-David
authors.initials: MD
authors.lastname: Ruepp
authors.forename: Hans
authors.initials: H
authors.lastname: Imboden
authors.forename: Isabelle
authors.initials: I
authors.lastname: Barde
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
authors.forename: Daniel
authors.initials: D
authors.lastname: Schümperli
mesh_terms: D000818:Animals; D001483:Base Sequence; D005091:Exons; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D012326:RNA Splicing; D012342:RNA, Small Nuclear / Q000235:genetics / Q000627:therapeutic use*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D012342:RNA, Small Nuclear; D055540:Survival of Motor Neuron 2 Protein; C405487:U7 small nuclear RNA