Journal
HUMAN MOLECULAR GENETICS
Volume 30, Issue 24, Pages 2456-2468Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddab194
Keywords
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Funding
- National Institutes of Health Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [ZIA HD008989]
- National Human Genome Research Institute [1ZIAHG000068-15]
- NHGRI Intramural Research Training Award
- NIH Oxford-Cambridge Scholars Program
- Medical Scientist Training Program from the University of Wisconsin-Madison School of Medicine and Public Health [3T32GM008692]
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The study analyzed RNA-Seq data from 42 NPC1 patient-derived fibroblast cell lines and identified 485 HP beta CD-responsive genes, showing significant involvement in cholesterol and lipid biosynthesis pathways. Experimental results in mice suggested that a gene, GPNMB, may serve as a useful biomarker of treatment response in NPC1 disease.
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-beta-cyclodextrin (HP beta CD), a compound currently under investigation in clinical trials. A total of 485 HP beta CD-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 HP beta CD 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 HP beta CD treatment.
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