Small molecule experimental treatments of Niemann-Pick A/B disease in cell-based models

细胞模型中 Niemann-Pick A/B 病的小分子实验治疗

• 批准号: 513549747
• 负责人: Professor Dr. Christoph Arenz
• 金额: --
• 依托单位: Arbeitsgruppe Organische und Bioorganische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/513549747?language=en
• 关键词: Small; molecule; experimental; treatments; Niemann

The goal of this project is to develop small-molecules for a potential treatment and diagnosis of Niemann-Pick Disease of types A and B (NPD A/B). As a prerequisite, adequate cellular disease models will be established using CRISPR/Cas9 or so-called base modifiers. Previous evidence from our group and from others clearly suggests that in NPD A/B cases sufficient protein is produced. Moreover, some of the most prevalent ASM variants are active in catalysis, if the protein is overexpressed from Sf9 cells and purfied. Assaying of ASM in intact living cells, which are homo-allelic for the most common NPD mutations will be key for the identification of molecules that can reconstitute ASM activity in NPD and might ameliorate pathology. Towards the latter goal, we plan to adapt and optimize our FRET probe-based flow cytometry assay for maximum sensitivity. Promising compounds will be characterized by lipidomics with an option to later test them in patient-derived cells or in living mice.

本项目的目标是开发用于治疗和诊断A型和B型尼曼-匹克病（NPD A/B）的小分子药物。作为先决条件，将使用CRISPR/Cas9或所谓的碱基修饰剂建立适当的细胞疾病模型。我们小组和其他人以前的证据清楚地表明，在NPD A/B病例中产生了足够的蛋白质。此外，如果从Sf 9细胞过表达并纯化蛋白质，则一些最普遍的ASM变体在催化中具有活性。在完整的活细胞中测定ASM，这是最常见的NPD突变的同源等位基因，将是鉴定可以在NPD中重建ASM活性并可能改善病理的分子的关键。为了实现后一个目标，我们计划调整和优化我们的FRET探针为基础的流式细胞术检测最大的灵敏度。有前途的化合物将通过脂质组学来表征，并可以选择稍后在患者来源的细胞或活小鼠中对其进行测试。