title: Spinal muscular atrophy and therapeutic prospects.
abstract: The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1). The SMN2 gene, a nearly identical copy of SMN1, has been detected as a promising target for SMA therapy. Both genes are ubiquitously expressed and encode identical proteins, but markedly differ in their splicing patterns: While SMN1 produces full-length (FL)-SMN transcripts only, the majority of SMN2 transcripts lacks exon 7. Transcriptional SMN2 activation or modulation of its splicing pattern to increase FL-SMN levels is believed to be clinically beneficial and therefore a crucial challenge in SMA research. Drugs such as valproic acid, phenylbutyrate, sodium butyrate, M344 and SAHA that mainly act as histone deacetylase inhibitors can mediate both: they stimulate the SMN2 gene transcription and/or restore the splicing pattern, thereby elevating the levels of FL-SMN2 protein. Preliminary phase II clinical trials and individual experimental curative approaches SMA patients show promising results. However, phase III double-blind placebo controlled clinical trials have to finally prove the efficacy of these drugs.
authors.affiliation: Institute of Human Genetics, Institute of Genetics, and Center for Molecular Medicine Cologne, University of Cologne, Kerpener Str. 34, 50931 Cologne, Germany.
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
authors.forename: Lars
authors.initials: L
authors.lastname: Brichta
authors.forename: Eric
authors.initials: E
authors.lastname: Hahnen
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein