Suzuki Keisuke, Banno Haruhiko, Katsuno Masahisa, Adachi Hiroaki, Tanaka Fumiaki, Sobue Gen
Department of Neurology, Nagoya University Graduate School of Medicine, Japan.
Brain Nerve. 2012 Mar;64(3):237-44.
Neurodegenerative diseases have long been construed as incurable disorders. However, therapeutic developments for these diseases are now facing a turning point, that is, analyses of cellular and animal models have provided insights into the pathogenesis of neurodegenerative diseases and have indicated rational therapeutic approaches. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease characterized by slowly progressive muscle weakness and atrophy. This disease is caused by the expansion of a trinucleotide CAG repeat within the androgen receptor (AR) gene. The results of animal studies suggest that testosterone-dependent nuclear accumulation of the pathogenic AR protein is a fundamental step in the neurodegenerative process. Androgen deprivation with a luteinizing hormone-releasing hormone (LHRH) analogue suppresses the toxicity of the mutant AR in animal models of SBMA. In a phase 3 trial, 48 weeks of treatment with leuprorelin acetate, an LHRH analogue, tended to improve swallowing function in a subgroup of SBMA patients with disease duration less than 10 years but did not significantly affect the total population. Disease duration might influence the efficacy of leuprorelin acetate, and therefore, a further clinical trial that involves sensitive outcome measures is in progress. Advances in basic and clinical research on SBMA are now paving the way for the clinical application of pathogenesis-targeting therapies. To optimize translational research related to the process of testing candidate therapies in humans, it is important to identify biomarkers that can be used as surrogate endpoints in clinical trials for neurodegenerative diseases.
神经退行性疾病长期以来一直被视为无法治愈的疾病。然而，这些疾病的治疗发展现在正面临一个转折点，也就是说，对细胞和动物模型的分析为神经退行性疾病的发病机制提供了见解，并指出了合理的治疗方法。脊髓延髓肌肉萎缩症（SBMA）是一种成人发病的运动神经元疾病，其特征是进行性肌肉无力和萎缩。这种疾病是由雄激素受体（AR）基因内的三核苷酸CAG重复序列扩增引起的。动物研究结果表明，致病性AR蛋白的睾酮依赖性核积累是神经退行性过程中的一个基本步骤。使用促黄体生成素释放激素（LHRH）类似物进行雄激素剥夺可抑制SBMA动物模型中突变AR的毒性。在一项3期试验中，使用LHRH类似物醋酸亮丙瑞林治疗48周，在疾病持续时间小于10年的SBMA患者亚组中倾向于改善吞咽功能，但对总体人群没有显著影响。疾病持续时间可能会影响醋酸亮丙瑞林的疗效，因此，一项涉及敏感结局指标的进一步临床试验正在进行中。SBMA基础和临床研究的进展现在为针对发病机制的疗法的临床应用铺平了道路。为了优化与在人体中测试候选疗法的过程相关的转化研究，识别可作为神经退行性疾病临床试验替代终点的生物标志物非常重要。
