臨床神経学

会長講演

神経変性疾患の分子標的治療を目指して

祖父江 元

名古屋大学大学院医学系研究科神経内科学〔〒466―8550 名古屋市昭和区鶴舞町65〕

Although recent advancements in molecular biology have provided increasing insights into the pathophysiology of neurodegenerative diseases, there is almost no disease-modifying therapy for which the efficacy has been verified in clinical trials. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by the expansion of a trinucleotide CAG repeat in the androgen receptor (AR) gene. SBMA exclusively affects males, whereas does not manifest in the females homozygous for the AR mutation. The ligand-dependent nuclear accumulation of pathogenic AR protein is central to the pathogenesis, although additional steps such as inter- and intra-molecular interaction are also required for toxicity. Leuprorelin, a luteinizing hormone-releasing hormone (LHRH) analogue that suppresses testosterone production from testis, inhibits toxic accumulation of pathogenic AR, thereby mitigating histopathological and behavioral impairments in a mouse model of SBMA. Although a randomized placebo-controlled multi-centric clinical trial showed no definite effect of the drug on motor functions, there was the improvement of swallowing function in a subgroup of patients whose disease duration was less than 10 years. These results indicate a need to elucidate the entire disease mechanism, clarify the natural history, initiate therapeutic intervention at an early stage, and develop sensitive outcome measures to evaluate drug effect.
Full Text of this Article in Japanese PDF (314K)

(臨床神経, 51:821−824, 2011)
key words:神経変性疾患,分子標的治療,トランスレーショナルリサーチ,自然歴,エンドポイント

(受付日:2011年5月18日)