title: Targeted Molecular Therapies for SBMA.
abstract: Spinal and bulbar muscular atrophy (SBMA) is a late-onset neuromuscular disease caused by a polyglutamine expansion in the androgen receptor gene which results in progressive spinal and bulbar motor neuron degeneration, and muscle atrophy. Although the causative genetic defect is known, until recently, the molecular pathogenesis of the disease was unclear, resulting in few, if any, targets for therapy development. However, over the past decade, our understanding of the pathomechanisms that play a role in SBMA has increased dramatically, and several of these pathways and mechanisms have now been investigated as possible therapeutic targets. In this review, we discuss some of the key pathomechanisms implicated in SBMA and describe some of the therapeutic strategies that have been tested in SBMA to date, which fall into four main categories: (i) gene silencing; (ii) protein quality control and/or increased protein degradation; (iii) androgen deprivation; and (iv) modulation of AR function. Finally, it is also now clear that in addition to a greater understanding of the molecular mechanisms that underlie disease, the development of an effective disease modifying therapy for SBMA will require the coordinated, collaborative effort of research teams with diverse areas of expertise, clinicians, pharmaceutical companies as well as patient groups.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3QX, UK. carlo.rinaldi@dpag.ox.ac.uk.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rinaldi
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, Queen Square, London, WC1N 3BG, UK.
authors.forename: Bilal
authors.initials: B
authors.lastname: Malik
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, Queen Square, London, WC1N 3BG, UK.|MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
mesh_terms: D000818:Animals; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000235:genetics / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism
chemical_list: D011944:Receptors, Androgen
keywords: Drug target; Molecular pathogenesis; Neuromuscular disease; Spinal and bulbar muscular atrophy