Therapeutics development for spinal muscular atrophy.
Spinal muscular atrophy is an autosomal recessive motor neuron disease that is the leading inherited cause of infant and early childhood mortality. Spinal muscular atrophy is caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1), but all patients retain a centromeric copy of the gene, SMN2. SMN2 produces reduced amounts of full-length SMN mRNA, and spinal muscular atrophy likely results from insufficient levels of SMN protein in motor neurons. The SMN protein plays a well-established role in assembly of the spliceosome and may also mediate mRNA trafficking in the axon and nerve terminus of neurons. In patients, spinal muscular atrophy disease severity correlates inversely with increased SMN2 gene copy number and, in transgenic mice lacking endogenous SMN, increasing SMN2 gene copy number from two to eight prevents the SMA disease phenotype. These observations suggest that increasing SMN expression levels may be beneficial to SMA patients. Currently pursued therapeutic strategies for SMA include induction of SMN2 gene expression, modulation of splicing of SMN2-derived transcripts, stabilization of SMN protein, neuroprotection of SMN deficit neurons, and SMN1 gene replacement. Early clinical trials of candidate therapeutics are now ongoing in SMA patients. Clinical trials in this disease present a unique set of challenges, including the development of meaningful outcome measures and disease biomarkers.
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Charlotte J
CJ
Sumner
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D018696:Neuroprotective Agents / Q000627:therapeutic use; D016601:RNA-Binding Proteins / Q000235:genetics; D055532:SMN Complex Proteins; D033581:Stem Cell Transplantation; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; 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