Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study.
Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study.
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DOI：
10.1002/acn3.292
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发表时间：
2016-03
影响因子：
5.3
通讯作者：
Suzuki Y
中科院分区：
文献类型：
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作者：
Narita A;Shirai K;Itamura S;Matsuda A;Ishihara A;Matsushita K;Fukuda C;Kubota N;Takayama R;Shigematsu H;Hayashi A;Kumada T;Yuge K;Watanabe Y;Kosugi S;Nishida H;Kimura Y;Endo Y;Higaki K;Nanba E;Nishimura Y;Tamasaki A;Togawa M;Saito Y;Maegaki Y;Ohno K;Suzuki Y
戈谢病（GD）是一种以葡萄糖脑苷脂酶缺乏为特征的溶酶体储积病。虽然酶替代和底物减少疗法是可用的，但它们在治疗GD神经系统表现方面的疗效可忽略不计。药理学伴侣治疗被假设为治疗这种疾病的神经系统表现提供了一种新的策略。具体而言，氨溴索，一种常用的祛痰剂，已被提议作为候选药理伴侣。本研究的目的是评价氨溴索在神经病性GD患者中的安全性、耐受性和神经学疗效。这项开放标签初步研究纳入了5例接受高剂量口服氨溴索联合酶替代治疗的患者。通过不良事件查询、体格检查、心电图、实验室研究和药物浓度评估安全性。通过淋巴细胞中葡萄糖脑苷脂酶活性和脑脊液中葡萄糖鞘氨醇水平的证据评估生化疗效。采用统一肌阵挛评定量表、粗大运动功能测量、功能独立性测量、癫痫发作频率、瞳孔对光反射、水平扫视潜伏期和电生理学研究评价神经系统疗效。高剂量口服氨溴索具有良好的安全性和耐受性，显著增加淋巴细胞葡萄糖脑苷脂酶活性，渗透血脑屏障，降低脑脊液中的葡萄糖鞘氨醇水平。所有患者的肌阵挛、癫痫发作和瞳孔对光反射功能障碍均明显改善。肌阵挛的缓解使两名患者的大运动功能得到了令人印象深刻的恢复，使他们能够再次行走。高剂量口服氨溴索的药理学伴侣治疗显示出治疗神经病性GD的前景，需要进一步的临床试验。
Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme‐replacement and substrate‐reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD. This open‐label pilot study included five patients who received high‐dose oral ambroxol in combination with enzyme replacement therapy. Safety was assessed by adverse event query, physical examination, electrocardiography, laboratory studies, and drug concentration. Biochemical efficacy was assessed through evidence of glucocerebrosidase activity in the lymphocytes and glucosylsphingosine levels in the cerebrospinal fluid. Neurological efficacy was evaluated using the Unified Myoclonus Rating Scale, Gross Motor Function Measure, Functional Independence Measure, seizure frequency, pupillary light reflex, horizontal saccadic latency, and electrophysiologic studies. High‐dose oral ambroxol had good safety and tolerability, significantly increased lymphocyte glucocerebrosidase activity, permeated the blood–brain barrier, and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all patients. Relief from myoclonus led to impressive recovery of gross motor function in two patients, allowing them to walk again. Pharmacological chaperone therapy with high‐dose oral ambroxol shows promise in treating neuronopathic GD, necessitating further clinical trials.