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Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide.

Authors
  • Howell, Matthew D1
  • Ottesen, Eric W1
  • Singh, Natalia N1
  • Anderson, Rachel L1
  • Singh, Ravindra N2
  • 1 Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA.
  • 2 Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA. Electronic address: [email protected]
Type
Published Article
Journal
Molecular Therapy
Publisher
Elsevier
Publication Date
Jun 07, 2017
Volume
25
Issue
6
Pages
1328–1341
Identifiers
DOI: 10.1016/j.ymthe.2017.03.036
PMID: 28412171
Source
Medline
Keywords
License
Unknown

Abstract

Spinal muscular atrophy (SMA), the leading genetic disease of children, is caused by low levels of survival motor neuron (SMN) protein. Here, we employ A15/283, an antisense oligonucleotide targeting a deep intronic sequence/structure, to examine the impact of restoration of SMN in a mild SMA mouse model. We show gender-specific amelioration of tail necrosis upon subcutaneous administrations of A15/283 into SMA mice at postnatal days 1 and 3. We also demonstrate that a modest increase in SMN due to early administrations of A15/283 dramatically improves testicular development and spermatogenesis. Our results reveal near total correction of expression of several genes in adult testis upon temporary increase in SMN during early postnatal development. This is the first demonstration of in vivo efficacy of an antisense oligonucleotide targeting a deep intronic sequence/structure. This is also the first report of gender-specific amelioration of SMA pathology upon a modest peripheral increase of SMN.

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