[Molecular-targeted therapies for spinal and bulbar muscular atrophy]

Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine-mediated lower motor neuron disease characterized by slowly progressive muscle weakness and atrophy. The cause of this disease is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. SBMA exclusively occurs in adult males, whereas both heterozygous and homozygous females are usually asymptomatic. Testosterone-dependent nuclear accumulation of the pathogenic AR protein has been considered to be a fundamental step of neurodegenerative process, which is followed by several molecular events such as transcriptional dysregulation, axonal transport disruption, and mitochondria dysfunction. Androgen deprivation suppresses the toxicity of the mutant AR in animal models of SBMA, and these insights have been translated to clinic. Animal studies have also suggested that activation of protein quality control systems are potential therapies for SBMA. To optimize "proof of concept", the process for testing candidate therapies in humans, it is of importance to identify responders to each therapy, to initiate interventions in early stages of the disease, and to establish biomarkers which can be used for evaluating the efficacy of treatment.