Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.
Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.
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DOI：
10.1016/s0140-6736(17)31465-4
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发表时间：
2017-10-14
期刊：
影响因子：
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通讯作者：
Porter FD
中科院分区：
文献类型：
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作者：
Ory DS;Ottinger EA;Farhat NY;King KA;Jiang X;Weissfeld L;Berry-Kravis E;Davidson CD;Bianconi S;Keener LA;Rao R;Soldatos A;Sidhu R;Walters KA;Xu X;Thurm A;Solomon B;Pavan WJ;Machielse BN;Kao M;Silber SA;McKew JC;Brewer CC;Vite CH;Walkley SU;Austin CP;Porter FD
C1 型尼曼-皮克病 (NPC1) 是一种溶酶体贮积病，其特征是进行性神经变性。在临床前测试中，2-羟丙基-β-环糊精 (HPβCD) 显着延迟了 NPC1 小鼠和猫模型中小脑浦肯野细胞的丢失，减缓了神经系统体征的进展，并延长了寿命。在一项开放标签、剂量递增 1/2a 期研究中评估了鞘内 HPβCD 的安全性和临床疗效。在 14 名神经系统受影响的 NPC1 参与者中评估了 50-1200 mg 的鞘内剂量，每月接受治疗 12 至 18 个月。另外三名参与者每两周接受一次治疗，持续 18 个月。对血清和脑脊液 24(S)-羟基胆固醇（作为靶标参与的生物标志物）和脑脊液蛋白质生物标志物进行了评估。 NPC 神经严重程度评分 (NSS) 用于比较 HPβCD 治疗的参与者与由 21 名相似年龄范围的 NPC1 参与者组成的历史比较队列的疾病进展情况。没有观察到与药物相关的严重不良事件。中高频听力损失（一种预期的不良事件）已被记录。当使用助听器进行管理时，这对日常交流并没有产生明显的影响。生物标志物研究与神经元胆固醇稳态的改善和神经元病理学的减少一致。每月接受治疗的 14 名参与者的 NSS 评分以每年 122 ± 0 34 分的速度增加，而对照组为 2 92 ± 0 27 分/年 (p=0 0002)。观察到行走 (p=0.0622)、认知 (p=0.0040) 和言语 (p=0.0423) 的 NSS 领域进展减缓。这项鞘内 HPβCD 治疗 NPC1 的 1/2a 期研究证明了可接受的安全性并减缓了疾病进展。
Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterized by progressive neurodegeneration. In preclinical testing 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological signs, and increased lifespan in murine and feline models of NPC1. Safety and clinical efficacy of intrathecal HPβCD were evaluated in an open-label, dose- escalation phase 1/2a study. Intrathecal doses ranging from 50–1200 mg were evaluated in 14 neurologically affected NPC1 participants treated monthly for 12 to 18 months. Three additional participants were treated every two weeks for 18 months. Serum and CSF 24(S)- hydroxycholesterol, which served as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range. No drug-related serious adverse events were observed. Mid- to high-frequency hearing loss, an expected adverse event, was documented. When managed with hearing aids, this did not have an appreciable impact on daily communication. Biomarker studies were consistent with improved neuronal cholesterol homeostasis and decreased neuronal pathology. The NSS score for the 14 participants treated monthly increased at a rate of 122 ± 0 34 points/year compared to 2 92 ± 0 27 points/year (p=0 0002) for the comparison group. Decreased progression was observed for NSS domains of ambulation (p=0 0622), cognition (p=0 0040) and speech (p=0 0423). This phase 1/2a study of intrathecal HPβCD for the treatment of NPC1 demonstrated an acceptable safety profile and slowing of disease progression.