Therapeutic approaches to spinal and bulbar muscular atrophy.
Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by trinucleotide repeat expansion in the androgen receptor gene. The disease mechanism probably involves a toxic gain of function in the mutant protein, because other mutations that cause a loss of androgen receptor function result in a different phenotype and the mutant protein is toxic in mouse models. In these models, the toxicity is ligand-dependent and is associated with protein aggregation, as well as altered transcriptional regulation, axonal transport and mitochondrial function. Various therapeutic approaches have shown efficacy in mouse models, including androgen reduction, heat shock protein 90 (HSP90) inhibition and insulin-like growth factor (IGF)-1 overexpression. Clinical trials of androgen-reducing agents have had mixed results, with indications of efficacy but no proof of clinically meaningful benefit to date. These clinical studies have established outcome measures for future trials of other agents that have been beneficial in animal studies.
Ranganathan
Srikanth
S
Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC A10, 221 84 Lund, Sweden.
Fischbeck
Kenneth H
KH
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D016472:Motor Neuron Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
D000726:Androgen Antagonists; D018841:HSP90 Heat-Shock Proteins; D018970:Insulin-Like Growth Factor Binding Protein 1; D018832:Molecular Chaperones; D011944:Receptors, Androgen