球脊髄性筋萎縮症の病態と治療法の開発

抄録

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is an adult–onset neuromuscular disease caused by an expansion of a CAG triplet–repeat within the first exon of the androgen receptor gene. Recent studies have indicated that SBMA is not a pure neurodegenerative disease, but affecting various non–neuronal tissues, including skeletal muscle. Furthermore, impairment in the interaction between motor neurons and skeletal muscles may be the key mechanism underlying the pathophysiology of SBMA. In the presence of testosterone, a disease–causing abnormal AR protein accumulates in the brainstem, spinal anterior horn, skeletal muscle, and several peripheral organs ; this induces a variety of symptoms, such as bulbar and muscular atrophy, liver dysfunction, and arrhythmia, in patients with SBMA. Studies using animal models have resulted in the development of promising therapeutic strategies for SBMA, including 1) testosterone suppression, 2) mutant androgen receptor gene silencing, 3) activation of protein quality control, and 4) rescuing of mitochondrial function. Efficacy of physical therapy has also been tested in small–scale clinical trials. In this review, we describe the clinical features and pathogenesis of SBMA, and summarize the therapeutic drug targets developed on the basis of results from recent studies using the well–established mouse models for this neuromuscular disease. Strategies for the development of disease–modifying therapy supported by basic experiments as well as well–planned clinical trials may lead to a breakthrough in the therapy for SBMA.