Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Medical Scientist Training Program, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53705, USA.
Hum Mol Genet. 2021 Nov 30;30(24):2456-2468. doi: 10.1093/hmg/ddab194.
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.
尼曼-皮克病 C1 型（NPC1）是一种罕见的致命神经退行性疾病，由溶酶体中未酯化胆固醇和糖脂的积累引起。这些亚细胞病理学导致肝脾肿大、神经退行性变和过早死亡的表型。NPC1 的临床表现的时间和严重程度差异极大。本研究分析了 42 例 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）治疗后诱导的转录变化，HPβCD 是一种正在临床试验中研究的化合物。共鉴定出 485 个 HPβCD 反应基因。这些基因的通路富集分析表明，它们与胆固醇和脂质生物合成有显著的关联。此外，对经 HPβCD 和腺相关病毒基因治疗处理的 Npc1m1N 基因敲除小鼠小脑进行免疫组织化学染色以及测量血浆，表明鉴定出的基因之一 GPNMB 可能是 NPC1 疾病治疗反应的有用生物标志物。总体而言，这个大型 NPC1 患者来源数据集为理解 HPβCD 治疗的基因组反应提供了全面的基础。
