Banno Haruhiko, Katsuno Masahisa, Suzuki Keisuke, Takeuchi Yu, Kawashima Motoshi, Suga Noriaki, Takamori Motoko, Ito Mizuki, Nakamura Tomohiko, Matsuo Koji, Yamada Shinichi, Oki Yumiko, Adachi Hiroaki, Minamiyama Makoto, Waza Masahiro, Atsuta Naoki, Watanabe Hirohisa, Fujimoto Yasushi, Nakashima Tsutomu, Tanaka Fumiaki, Doyu Manabu, Sobue Gen
Department of Neurology, Nagoya University Graduate School of Medicine, Aichi, Japan.
Ann Neurol. 2009 Feb;65(2):140-50. doi: 10.1002/ana.21540.
Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Animal studies have shown that the pathogenesis of SBMA is dependent on serum testosterone level. This study is aimed at evaluating the efficacy and safety of androgen deprivation by leuprorelin acetate in patients with SBMA.
Fifty SBMA patients underwent subcutaneous injections of leuprorelin acetate or placebo in a randomized, placebo-controlled trial for 48 weeks, followed by an open-label trial for an additional 96 weeks, in which 19 patients of the leuprorelin group and 15 of the placebo group received leuprorelin acetate. The patients who did not participate in the open-label trial were also followed up for the 96-week period (UMIN000000474).
Leuprorelin acetate significantly extended the duration of cricopharyngeal opening in videofluorography and decreased mutant AR accumulation in scrotal skin biopsy. The patients treated with leuprorelin acetate for 144 weeks exhibited significantly greater functional scores and better swallowing parameters than those who received placebo. Autopsy of one patient who received leuprorelin acetate for 118 weeks suggested that androgen deprivation inhibits the nuclear accumulation or stabilization, or both, of mutant AR in the motor neurons of the spinal cord and brainstem.
These observations suggest that administration of leuprorelin acetate suppresses the deterioration of neuromuscular impairment in SBMA by inhibiting the toxic accumulation of mutant AR. The results of this phase 2 trial support the start of large-scale clinical trials of androgen deprivation for SBMA.
脊髓延髓性肌萎缩症（SBMA）是一种遗传性运动神经元疾病，由雄激素受体（AR）中多聚谷氨酰胺序列的扩增引起。动物研究表明，SBMA的发病机制取决于血清睾酮水平。本研究旨在评估醋酸亮丙瑞林去势治疗SBMA患者的疗效和安全性。
50例SBMA患者在一项随机、安慰剂对照试验中接受皮下注射醋酸亮丙瑞林或安慰剂，为期48周，随后进行为期96周的开放标签试验，其中醋酸亮丙瑞林组19例患者和安慰剂组15例患者接受醋酸亮丙瑞林治疗。未参与开放标签试验的患者也进行了96周的随访（UMIN000000474）。
醋酸亮丙瑞林显著延长了电视荧光吞咽造影检查中环咽肌开放的持续时间，并减少了阴囊皮肤活检中突变型AR的积累。接受醋酸亮丙瑞林治疗144周的患者比接受安慰剂的患者表现出显著更高的功能评分和更好的吞咽参数。对一名接受醋酸亮丙瑞林治疗118周的患者进行尸检表明，去势抑制了脊髓和脑干运动神经元中突变型AR的核积累或稳定，或两者兼有。
这些观察结果表明，醋酸亮丙瑞林给药通过抑制突变型AR的毒性积累来抑制SBMA中神经肌肉损伤的恶化。这项2期试验的结果支持开始针对SBMA进行去势的大规模临床试验。
