title: MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy.
abstract: Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in the disease mechanism; therefore, reducing the mutant protein holds promise as an effective treatment strategy. In this work, we evaluated a microRNA (miRNA) to reduce AR expression. From a list of predicted miRNAs that target human AR, we selected microRNA-298 (miR-298) for its ability to downregulate AR mRNA and protein levels when transfected in cells overexpressing wild-type and mutant AR and in SBMA patient-derived fibroblasts. We showed that miR-298 directly binds to the 3'-untranslated region of the human AR transcript, and counteracts AR toxicity in vitro. Intravenous delivery of miR-298 with adeno-associated virus serotype 9 vector resulted in efficient transduction of muscle and spinal cord and amelioration of the disease phenotype in SBMA mice. Our findings support the development of miRNAs as a therapeutic strategy for SBMA and other neurodegenerative disorders caused by toxic proteins.
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Naemeh
authors.initials: N
authors.lastname: Pourshafie
authors.affiliation: Section on Nervous System Development and Plasticity, The Eunice Kennedy Shriver National Institute of Child and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Lee
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ke-Lian
authors.initials: KL
authors.lastname: Chen
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: George G
authors.initials: GG
authors.lastname: Harmison
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Bott
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Brain and Mind Research Center, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, Maryland, USA.
authors.forename: Barrington G
authors.initials: BG
authors.lastname: Burnett
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.|Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rinaldi
mesh_terms: D020413:3' Untranslated Regions; D061605:Administration, Intravenous; D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000628:therapy*; D011944:Receptors, Androgen / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C410798:AR protein, human; C569760:MIRN298 microRNA, human; D035683:MicroRNAs; D011944:Receptors, Androgen