The rare, fatal neurodegenerative disorder Niemann-Pick disease type C1 (NPC1) arises from lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. The timing and severity of NPC1 clinical presentation is extremely heterogeneous. This study analyzed RNA-Seq data from 42 NPC1 patient-derived, primary fibroblast cell lines to determine transcriptional changes induced by treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a compound currently under investigation in clinical trials. A total of 485 HPβCD-responsive genes were identified. Pathway enrichment analysis of these genes showed significant involvement in cholesterol and lipid biosynthesis. Furthermore, immunohistochemistry of the cerebellum as well as measurements of plasma from Npc1m1N null mice treated with HPβCD and adeno-associated virus gene therapy suggests that one of the identified genes, GPNMB, may serve as a useful biomarker of treatment response in NPC1 disease. Overall, this large NPC1 patient-derived dataset provides a comprehensive foundation for understanding the genomic response to HPβCD treatment.

中文翻译：

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HPβCD 处理的 Niemann-Pick 病 C1 型细胞的转录组强调 GPNMB 作为治疗的生物标志物。

罕见的致命神经退行性疾病 C1 型 (NPC1) 是由未酯化胆固醇和鞘糖脂的溶酶体积累引起的。这些亚细胞病理导致肝脾肿大、神经变性和过早死亡的表型。NPC1 临床表现的时间和严重程度极其不同。本研究分析了来自 42 个 NPC1 患者来源的原代成纤维细胞系的 RNA-Seq 数据，以确定用 2-羟丙基-β-环糊精 (HPβCD) 治疗诱导的转录变化，该化合物目前正在临床试验中进行研究。共鉴定出 485 个 HPβCD 反应基因。这些基因的通路富集分析显示在胆固醇和脂质生物合成中具有重要作用。此外，小脑的免疫组织化学以及用 HPβCD 和腺相关病毒基因治疗治疗的 Npc1m1N 缺失小鼠的血浆测量表明，已识别的基因之一 GPNMB 可能作为 NPC1 疾病治疗反应的有用生物标志物。总体而言，这个大型 NPC1 患者衍生数据集为了解基因组对 HPβCD 治疗的反应提供了全面的基础。