Orphazyme A/S, Ole Maaloes vej 3, DK-2200 Copenhagen, Denmark.
Regional Coordinator Centre for Rare Diseases, Academic Hospital "Santa Maria della Misericordia", Udine, Italy.
EBioMedicine. 2018 Dec;38:142-153. doi: 10.1016/j.ebiom.2018.11.037. Epub 2018 Nov 27.
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.
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.
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.
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.
The research was funded by Orphazyme A/S, Copenhagen, Denmark.
戈谢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催化活性来影响 GCase 功能。热休克蛋白是众所周知的细胞保护分子，具有蛋白质稳态和溶酶体功能，其操纵被认为是 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里莫氯醇是一种特征明确的 HSP 放大器，已进行了广泛的临床测试。重要的是，阿里莫氯醇能有效地穿过血脑屏障，为治疗 GD 的神经表现提供了机会，而 GD 仍然没有一种可改变疾病的治疗方法。
我们使用一系列生物学和生化体外测定法，评估了阿里莫氯醇对 GD 患者原代成纤维细胞和类神经元细胞的体外系统中 GCase 活性的影响。
我们发现，阿里莫氯醇诱导了相关的 HSP，如内质网驻留 HSP70（BiP），并增强了几种基因型（包括 GD 患者原代细胞中的常见 L444P 和 N370S 突变）中突变 GCase 的折叠、成熟、活性和正确的细胞定位。这些效应在通过多能成体干细胞分化获得的 GD 人类神经元模型中得到了再现。
这些数据表明 HSP 靶向治疗在 GCase 缺乏症中的潜力，并强烈支持阿里莫氯醇作为 GD 的神经病变形式的潜在治疗选择的临床开发。
该研究由丹麦哥本哈根的 Orphazyme A/S 资助。
