Substrate reduction therapy using Genz‐667161 reduces levels of pathogenic components in a mouse model of neuronopathic forms of Gaucher disease,Journal of Neurochemistry

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Substrate reduction therapy using Genz‐667161 reduces levels of pathogenic components in a mouse model of neuronopathic forms of Gaucher disease
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2020-08-03 , DOI: 10.1111/jnc.15136
Shani Blumenreich ₁ , Chen Yaacobi ₁ , Ayelet Vardi ₁ , Or B Barav ₁ , Einat B Vitner ₂ , Hyejung Park ₃ , Bing Wang ₃ , Seng H Cheng ₄ , Sergio P Sardi ₄ , Anthony H Futerman ₁

Affiliation

Most lysosomal storage diseases (LSDs) have a significant neurological component, including types 2 and 3 Gaucher disease (neuronal forms of Gaucher disease; nGD). No therapies are currently available for nGD since the recombinant enzymes used in the systemic form of Gaucher disease do not cross the blood–brain barrier (BBB). However, a number of promising approaches are currently being tested, including substrate reduction therapy (SRT), in which partial inhibition of the synthesis of the glycosphingolipids (GSLs) that accumulate in nGD lowers their accumulation. We now induce nGD in mice by injection with conduritol B‐epoxide (CBE), an irreversible inhibitor of acid beta‐glucosidase (GCase), the enzyme defective in nGD, with or without co‐injection with Genz‐667161, a prototype for SRT which crosses the BBB. Significant neuropathology, and a reduction in lifespan, was observed upon CBE injection, and this was largely reversed by co‐injection with Genz‐667161, along with a reduction in glucosylceramide and glucosylsphingosine levels. Analysis of gene expression by RNAseq revealed that Genz‐667161 largely reversed the changes in genes and pathways that were differentially expressed upon CBE injection, specifically pathways of GSL metabolism, lipoproteins and other lipid metabolic pathways, lipid droplets, astrocyte activation, neuronal function, and to some extent, neuroinflammation. Together, this demonstrates the efficacy of SRT to reverse the effects of substrate accumulation on pathological components and pathways in nGD brain.

中文翻译：

使用Genz‐667161的底物减少疗法可降低神经病性高雪氏病小鼠模型中的致病成分水平

大多数溶酶体贮积病（LSD）具有重要的神经系统成分，包括2型和3型Gaucher病（神经元形式的Gaucher病； nGD）。nGD目前尚无疗法，因为用于全身性高雪氏病的重组酶不能穿越血脑屏障（BBB）。但是，目前正在测试许多有前途的方法，包括底物减少疗法（SRT），其中部分抑制累积在nGD中的糖鞘脂（GSL）的合成会降低其积聚。现在，我们通过注射conduritol B-环氧化物（CBE）（一种不可逆的酸性β-葡萄糖苷酶（GCase）抑制剂，nGD中的一种酶）诱导小鼠中的nGD，无论是否与SRT的原型Genz-667161共注射穿过BBB。重要的神经病理学注射CBE后观察到寿命降低，并且通过与Genz-667161共注射以及葡萄糖基神经酰胺和葡萄糖基鞘氨醇水平的降低在很大程度上被逆转。RNAseq对基因表达的分析显示，Genz-667161在很大程度上逆转了CBE注射后差异表达的基因和途径的变化，特别是GSL代谢，脂蛋白和其他脂质代谢途径，脂质滴，星形胶质细胞活化，神经元功能和在某种程度上是神经炎症。在一起，这证明了SRT可以逆转底物积累对nGD脑中病理成分和途径的影响。以及减少的葡萄糖基神经酰胺和葡萄糖基鞘氨醇水平。RNAseq对基因表达的分析显示，Genz-667161在很大程度上逆转了CBE注射后差异表达的基因和途径的变化，特别是GSL代谢，脂蛋白和其他脂质代谢途径，脂质滴，星形胶质细胞活化，神经元功能和在某种程度上是神经炎症。在一起，这证明了SRT可以逆转底物积累对nGD脑中病理成分和途径的影响。以及减少的葡萄糖基神经酰胺和葡萄糖基鞘氨醇水平。RNAseq对基因表达的分析显示，Genz-667161在很大程度上逆转了CBE注射后差异表达的基因和途径的变化，特别是GSL代谢，脂蛋白和其他脂质代谢途径，脂质滴，星形胶质细胞活化，神经元功能和在某种程度上是神经炎症。在一起，这证明了SRT可以逆转底物积累对nGD脑中病理成分和途径的影响。脂蛋白和其他脂类代谢途径，脂滴，星形胶质细胞活化，神经元功能以及某种程度上的神经炎症。在一起，这证明了SRT可以逆转底物积累对nGD脑中病理成分和途径的影响。脂蛋白和其他脂类代谢途径，脂滴，星形胶质细胞活化，神经元功能以及某种程度上的神经炎症。在一起，这证明了SRT可以逆转底物积累对nGD脑中病理成分和途径的影响。

更新日期：2020-08-03

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