Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2

Nat Med. 2012 Jul;18(7):1136-41. doi: 10.1038/nm.2791.


Spinal and bulbar muscular atrophy (SBMA) is an inherited neurodegenerative disorder caused by the expansion of the polyglutamine (polyQ) tract of the androgen receptor (AR-polyQ). Characteristics of SBMA include proximal muscular atrophy, weakness, contraction fasciculation and bulbar involvement. MicroRNAs (miRNAs) are a diverse class of highly conserved small RNA molecules that function as crucial regulators of gene expression in animals and plants. Recent functional studies have shown the potent activity of specific miRNAs as disease modifiers both in vitro and in vivo. Thus, potential therapeutic approaches that target the miRNA processing pathway have recently attracted attention. Here we describe a novel therapeutic approach using the adeno-associated virus (AAV) vector–mediated delivery of a specific miRNA for SBMA. We found that miR-196a enhanced the decay of the AR mRNA by silencing CUGBP, Elav-like family member 2 (CELF2). CELF2 directly acted on AR mRNA and enhanced the stability of AR mRNA. Furthermore, we found that the early intervention of miR-196a delivered by an AAV vector ameliorated the SBMA phenotypes in a mouse model. Our results establish the proof of principle that disease-specific miRNA delivery could be useful in neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Base Sequence
  • CELF Proteins
  • Dependovirus / genetics*
  • Exons / genetics
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Gene Silencing*
  • Genetic Therapy*
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • MicroRNAs / chemistry
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • MicroRNAs / therapeutic use
  • Middle Aged
  • Molecular Sequence Data
  • Muscular Atrophy, Spinal / genetics*
  • Muscular Atrophy, Spinal / pathology
  • Muscular Atrophy, Spinal / prevention & control*
  • Mutant Proteins / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Nucleic Acid Conformation
  • Phenotype
  • RNA Stability / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Rotarod Performance Test


  • CELF Proteins
  • CELF2 protein, human
  • MIRN196 microRNA, human
  • MicroRNAs
  • Mutant Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptors, Androgen