Patterson Marc C, Vecchio Darleen, Prady Helena, Abel Larry, Wraith James E
Department of Neurology and Pediatrics, Columbia University, NY, USA.
Lancet Neurol. 2007 Sep;6(9):765-72. doi: 10.1016/S1474-4422(07)70194-1.
Niemann-Pick type C disease (NPC) is an inherited neurodegenerative disorder characterised by an intracellular lipid-trafficking defect with secondary accumulation of glycosphingolipids. Miglustat, a small iminosugar, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis. Miglustat is able to cross the blood-brain barrier, and is thus a potential therapy for neurological diseases. We aimed to establish the effect of miglustat on several markers of NPC severity.
Patients aged 12 years or older who had NPC (n=29) were randomly assigned to receive either miglustat 200 mg three times a day (n=20) or standard care (n=9) for 12 months. 12 children younger than 12 years of age were included in an additional cohort; all received miglustat at a dose adjusted for body surface area. All participants were then treated with miglustat for an additional year in an extension study. The primary endpoint was horizontal saccadic eye movement (HSEM) velocity, based on its correlation with disease progression. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN26761144.
At 12 months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0.028). Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years. The safety and tolerability of miglustat 200 mg three times a day in study participants was consistent with previous trials in type I Gaucher disease, where half this dose was used.
Miglustat improves or stabilises several clinically relevant markers of NPC. This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit.
尼曼-匹克C型病（NPC）是一种遗传性神经退行性疾病，其特征为细胞内脂质转运缺陷以及鞘糖脂继发性蓄积。米格列醇是一种小分子亚氨基糖，可可逆性抑制葡糖神经酰胺合酶，该酶催化鞘糖脂合成的首个关键步骤。米格列醇能够穿过血脑屏障，因此是一种治疗神经疾病的潜在药物。我们旨在确定米格列醇对NPC严重程度的几种标志物的影响。
年龄在12岁及以上的NPC患者（n = 29）被随机分配，分别接受每日3次、每次200 mg米格列醇治疗（n = 20）或标准治疗（n = 9），为期12个月。另有一个队列纳入了12名12岁以下的儿童；所有儿童均接受根据体表面积调整剂量的米格列醇治疗。在一项延长期研究中，所有参与者随后再接受一年的米格列醇治疗。主要终点为水平扫视眼动（HSEM）速度，基于其与疾病进展的相关性。本研究已注册为一项国际标准随机对照试验，注册号为ISRCTN26761144。
在12个月时，接受米格列醇治疗的患者与接受标准治疗的患者相比，HSEM速度有所改善；排除服用苯二氮䓬类药物的患者后，结果具有显著性（p = 0.028）。12个月时，儿童的HSEM速度也有类似程度的改善。12岁以上接受治疗的患者在吞咽能力、稳定的听力以及动态指数恶化减缓方面也有改善。研究参与者每日3次服用每次200 mg米格列醇的安全性和耐受性与先前在I型戈谢病试验中一致，后者使用的剂量是本研究剂量的一半。
米格列醇可改善或稳定NPC的几种临床相关标志物。这是在NPC研究中首个有动物和临床数据支持具有疾病修饰益处的药物。
