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The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy.
d'Ydewalle, Constantin; Ramos, Daniel M; Pyles, Noah J; Ng, Shi-Yan; Gorz, Mariusz; Pilato, Celeste M; Ling, Karen; Kong, Lingling; Ward, Amanda J; Rubin, Lee L; Rigo, Frank; Bennett, C Frank; Sumner, Charlotte J.
Afiliação
  • d'Ydewalle C; Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
  • Ramos DM; Department of Neuroscience, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
  • Pyles NJ; Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
  • Ng SY; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Gorz M; Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
  • Pilato CM; Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
  • Ling K; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Kong L; Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
  • Ward AJ; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
  • Rubin LL; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • Rigo F; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Bennett CF; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Sumner CJ; Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA. Electronic address: csumner1@jhmi.edu.
Neuron ; 93(1): 66-79, 2017 Jan 04.
Article em En | MEDLINE | ID: mdl-28017471
ABSTRACT
The neuromuscular disorder spinal muscular atrophy (SMA), the most common inherited killer of infants, is caused by insufficient expression of survival motor neuron (SMN) protein. SMA therapeutics development efforts have focused on identifying strategies to increase SMN expression. We identified a long non-coding RNA (lncRNA) that arises from the antisense strand of SMN, SMN-AS1, which is enriched in neurons and transcriptionally represses SMN expression by recruiting the epigenetic Polycomb repressive complex-2. Targeted degradation of SMN-AS1 with antisense oligonucleotides (ASOs) increases SMN expression in patient-derived cells, cultured neurons, and the mouse central nervous system. SMN-AS1 ASOs delivered together with SMN2 splice-switching oligonucleotides additively increase SMN expression and improve survival of severe SMA mice. This study is the first proof of concept that targeting a lncRNA to transcriptionally activate SMN2 can be combined with SMN2 splicing modification to ameliorate SMA and demonstrates the promise of combinatorial ASOs for the treatment of neurogenetic disorders.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Atrofia Muscular Espinal / Regulação da Expressão Gênica / RNA Antissenso / Proteína 1 de Sobrevivência do Neurônio Motor / Proteína 2 de Sobrevivência do Neurônio Motor / RNA Longo não Codificante / Neurônios Motores Limite: Animals / Humans Idioma: En Revista: Neuron Assunto da revista: NEUROLOGIA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Atrofia Muscular Espinal / Regulação da Expressão Gênica / RNA Antissenso / Proteína 1 de Sobrevivência do Neurônio Motor / Proteína 2 de Sobrevivência do Neurônio Motor / RNA Longo não Codificante / Neurônios Motores Limite: Animals / Humans Idioma: En Revista: Neuron Assunto da revista: NEUROLOGIA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos