第51回日本神経学会総会
＜シンポジウム02―2＞アカデミア発の創薬・治療研究
球脊髄性筋萎縮症の分子標的治療
祖父江 元
名古屋大学神経内科〔〒466―8550 名古屋市昭和区鶴舞町65〕
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of SBMA 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 males, whereas both heterozygous and homozygous females are usually asymptomatic. In a transgenic mouse model of SBMA, neuromuscular symptoms are markedly pronounced in the male mice, but far less severe in the female counterparts. Androgen deprivation through both surgical and chemical castration substantially suppresses nuclear accumulation of the pathogenic AR, and thereby improves symptoms in the male mice. Since the nuclear translocation of AR is ligand-dependent, testosterone appears to show toxic effects by accelerating nuclear translocation of the pathogenic AR. In a phase 2 clinical trial, 12-month treatment with leuprorelin significantly diminished the serum level of creatine kinase, and suppressed nuclear accumulation of the pathogenic AR. The ligand-dependent accumulation of the pathogenic AR, an initial step in the neurodegenerative process in SBMA, is followed by several downstream molecular events such as transcriptional dysregulation, axonal transport disruption, and mitochondrial insufficiency, indicating that both upstream and downstream molecular abnormalities should be corrected.
Full Text of this Article in Japanese PDF (279K)
(臨床神経, 50：839−841, 2010)
key words：球脊髄性筋萎縮症，分子標的治療，リュープロレリン酢酸塩，TGF-β
（受付日：2010年5月21日）
