title: Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds.
abstract: Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Cherry
authors.forename: Erkan Y
authors.initials: EY
authors.lastname: Osman
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Evans
authors.forename: Sungwoon
authors.initials: S
authors.lastname: Choi
authors.forename: Xuechao
authors.initials: X
authors.lastname: Xing
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Marcie A
authors.initials: MA
authors.lastname: Glicksman
authors.forename: Christian L
authors.initials: CL
authors.lastname: Lorson
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Androphy
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055808:Drug Discovery; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D055533:Survival of Motor Neuron 1 Protein / Q000032:analysis / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000032:analysis / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D012333:RNA, Messenger; D054852:Small Molecule Libraries; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
keywords: SMA; SMN; SMN2; drug discovery; spinal muscular atrophy