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)1,2. Characteristics of SBMA include proximal muscular atrophy, weakness, contraction fasciculation and bulbar involvement3. MicroRNAs (miRNAs) are a diverse class of highly conserved small RNA molecules that function as crucial regulators of gene expression in animals and plants4. Recent functional studies have shown the potent activity of specific miRNAs as disease modifiers both in vitro and in vivo5,6,7,8. Thus, potential therapeutic approaches that target the miRNA processing pathway have recently attracted attention9,10. 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.
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We are grateful to T. Cooper (Department of Pathology and Immunology, Baylor College of Medicine) for kindly providing the plasmid expressing human CELF2. We also thank N. Takino, H. Miyauchi and K. Ayabe (Division of Neurology, Department of Medicine, Jichi Medical University) for their help with the production of the AAV vectors and Y. Kondo and K. Shinjo (Division of Molecular Oncology, Aichi Cancer Center Research Institute) for expert technical support and helpful discussions. This work was supported by grants from the Ministry of Health, Labor and Welfare; grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; a Center-of-Excellence (COE) grant; a Grant-in-Aid for Scientific Research on Innovated Areas “Foundations of Synapse and Neurocircuit Pathology”; and the Core Research for Evolutional Science and Technology (CREST) program of the Japan Science and Technology Agency (JST).
The authors declare no competing financial interests.
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Miyazaki, Y., Adachi, H., Katsuno, M. et al. Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2. Nat Med 18, 1136–1141 (2012). https://doi.org/10.1038/nm.2791
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