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首页> 外文期刊>EBioMedicine >The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidase
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The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidase

机译：热激蛋白放大器阿莫洛莫改善葡萄糖脑苷脂酶的重折叠，成熟和溶酶体活性

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Background Gaucher Disease is caused by mutations of the GBA gene which encodes the lysosomal enzyme acid beta-glucosidase (GCase). GBA mutations commonly affect GCase function by perturbing its protein homeostasis rather than its catalytic activity. Heat shock proteins are well known cytoprotective molecules with functions in protein homeostasis and lysosomal function and their manipulation has been suggested as a potential therapeutic strategy for GD. The investigational drug arimoclomol, which is in phase II/III clinical trials, is a well-characterized HSP amplifier and has been extensively clinically tested. Importantly, arimoclomol efficiently crosses the blood-brain-barrier presenting an opportunity to target the neurological manifestations of GD, which remains without a disease-modifying therapy. Methods We used a range of biological and biochemical in vitro assays to assess the effect of arimoclomol on GCase activity in ex vivo systems of primary fibroblasts and neuronal-like cells from GD patients. Findings We found that arimoclomol induced relevant HSPs such as ER-resident HSP70 (BiP) and enhanced the folding, maturation, activity, and correct cellular localization of mutated GCase across several genotypes including the common L444P and N370S mutations in primary cells from GD patients. These effects where recapitulated in a human neuronal model of GD obtained by differentiation of multipotent adult stem cells. Interpretation These data demonstrate the potential of HSP-targeting therapies in GCase-deficiencies and strongly support the clinical development of arimoclomol as a potential therapeutic option for the neuronopathic forms of GD. Funding The research was funded by Orphazyme A/S, Copenhagen, Denmark.
机译：背景高雪氏病是由编码溶酶体酶酸性β-葡萄糖苷酶（GCase）的GBA基因突变引起的。 GBA突变通常通过扰乱其蛋白质稳态而不是其催化活性来影响GCase的功能。热休克蛋白是众所周知的具有蛋白稳态和溶酶体功能的细胞保护分子，并且已经提出将其操纵作为GD的潜在治疗策略。正在进行II / III期临床试验的研究药物阿昔洛酚是一种特性良好的HSP放大器，并已进行了广泛的临床测试。重要的是，arimoclomol有效地穿过了血脑屏障，为靶向GD的神经学表现提供了机会，而GD无需进行任何改善疾病的治疗。方法我们使用了一系列生物和生化体外测定方法，评估了阿莫莫酚对GD患者原代成纤维细胞和神经元样细胞的离体系统中GCase活性的影响。研究结果我们发现，arimoclomol诱导了相关的HSP，例如ER驻留HSP70（BiP），并增强了GD基因在包括GD患者的原代细胞中常见的L444P和N370S突变在内的几种基因型的折叠，成熟，活性以及正确的突变GCase的细胞定位。在通过分化多能成体干细胞获得的GD人神经元模型中概括了这些作用。解释这些数据证明了针对HSP的疗法在GCase缺乏症中的潜力，并强烈支持阿利莫酚的临床开发，作为GD神经病变形式的潜在治疗选择。资助该研究由丹麦哥本哈根的Orphazyme A / S资助。

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