Clinical trials in spinal muscular atrophy.
OBJECTIVE
Spinal muscular atrophy is a neuromuscular disorder manifesting as weakness and hypotonia across a broad spectrum of severity. Mutations in the telomeric copy of the survival motor neuron gene (SMN1) cause the autosomal recessive form. Disease severity is modified by the number of centromeric copies of the gene (SMN2) and the quantity of survival motor neuron protein. This has given rise to a number of treatment strategies.


RESULTS
Histone deacetylase inhibitors appear to increase the expression of SMN2, with an increase in survival motor neuron protein in various cell types. Clinical trials have been performed with three histone deacetylase inhibitors which are already licensed in the USA. Phenylbutyrate showed promise in a mouse model and an open-label pilot study, but was not effective in a phase 2 trial. Valproate may enhance transcription and reverse SMN2 splicing pattern, and has induced promising motor-function improvement in patients. Hydroxyurea may enhance splice function and increase the number of nuclear 'gems', small nuclear organelles in which survival motor neuron protein concentrates.


CONCLUSIONS
Discoveries regarding the genetics and pathogenesis of spinal muscular atrophy have identified potential targets for pharmacotherapy, raising hope that better treatments will eventually be developed.
Darras
Basil T
BT
Department of Neurology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA. basil.darras@childrens.harvard.edu
Kang
Peter B
PB
D000818:Animals; D002648:Child; D002986:Clinical Trials as Topic; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D007223:Infant; D009046:Motor Neurons / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D019384:Nucleic Acid Synthesis Inhibitors / Q000627:therapeutic use; D010654:Phenylbutyrates / Q000627:therapeutic use; D016601:RNA-Binding Proteins / Q000235:genetics; D055532:SMN Complex Proteins; D014897:Spinal Muscular Atrophies of Childhood / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D014635:Valproic Acid / Q000627:therapeutic use
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D010654:Phenylbutyrates; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D014635:Valproic Acid; D006918:Hydroxyurea