Phase 2 Trial of Leuprorelin in Patients with Spinal and Bulbar Muscular Atrophy
Phase 2 Trial of Leuprorelin in Patients with Spinal and Bulbar Muscular Atrophy
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DOI：
10.1002/ana.21540
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发表时间：
2009-02-01
影响因子：
11.2
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Banno, Haruhiko;Katsuno, Masahisa;Sobue, Gen
目的：脊髓延髓肌萎缩症（SBMA）是一种遗传性运动神经元疾病，由雄激素受体（AR）中的多聚谷氨酰胺束扩张引起。动物实验表明，SBMA的发病机制依赖于血清睾酮水平。本研究旨在评价醋酸亮丙瑞林雄激素阻断治疗SBMA患者的疗效和安全性。在一项为期48周的随机化、安慰剂对照试验中，50例SBMA患者接受了醋酸亮丙瑞林或安慰剂皮下注射，随后进行了一项为期96周的开放标签试验，其中亮丙瑞林组19例患者和安慰剂组15例患者接受醋酸亮丙瑞林治疗。未参加开放标签试验的患者也随访了96周（UMIN00000474）。结果：醋酸亮丙瑞林显著延长了荧光透视检查中的颅咽开口持续时间，并减少了阴囊皮肤活检中的突变型AR蓄积。与接受安慰剂治疗的患者相比，接受醋酸亮丙瑞林治疗144周的患者表现出显著更高的功能评分和更好的吞咽参数。一名接受醋酸亮丙瑞林治疗118周的患者的尸检表明，雄激素剥夺抑制了脊髓和脑干运动神经元中突变型AR的核蓄积或稳定性，或两者兼而有之：这些观察结果表明，醋酸亮丙瑞林给药通过抑制突变型AR的毒性蓄积来抑制SBMA中神经肌肉损伤的恶化。这项2期试验的结果支持SBMA雄激素剥夺的大规模临床试验的开始。
Objective: 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.Methods: 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).Results: 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.Interpretation: 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.