title: Somatic Therapy of a Mouse SMA Model with a U7 snRNA Gene Correcting SMN2 Splicing.
abstract: Spinal Muscular Atrophy is due to the loss of SMN1 gene function. The duplicate gene SMN2 produces some, but not enough, SMN protein because most transcripts lack exon 7. Thus, promoting the inclusion of this exon is a therapeutic option. We show that a somatic gene therapy using the gene for a modified U7 RNA which stimulates this splicing has a profound and persistent therapeutic effect on the phenotype of a severe Spinal Muscular Atrophy mouse model. To this end, the U7 gene and vector and the production of pure, highly concentrated self-complementary (sc) adenovirus-associated virus 9 vector particles were optimized. Introduction of the functional vector into motoneurons of newborn Spinal Muscular Atrophy mice by intracerebroventricular injection led to a highly significant, dose-dependent increase in life span and improvement of muscle functions. Besides the central nervous system, the therapeutic U7 RNA was expressed in the heart and liver which may additionally have contributed to the observed therapeutic efficacy. This approach provides an additional therapeutic option for Spinal Muscular Atrophy and could also be adapted to treat other diseases of the central nervous system with regulatory small RNA genes.
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.|Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Odermatt
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors.forename: Judith
authors.initials: J
authors.lastname: Trüb
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Furrer
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.|Current address: Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Fricker
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Marti
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schümperli
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism; D012326:RNA Splicing; D012342:RNA, Small Nuclear / Q000008:administration & dosage* / Q000494:pharmacology; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics*
chemical_list: D012342:RNA, Small Nuclear; C000597152:SMN2 protein, mouse; D055540:Survival of Motor Neuron 2 Protein; C405487:U7 small nuclear RNA