The long term goal of this project is to identify the gene responsible for Niemann-Pick Type C (NP-C), to study its role in the pathogenesis of the disorder and to use this information to aid in the treatment of this disease. NP-C is an autosomal- recessive, neurovisceral lipid storage disorder and presents as variable hepatosplenomegaly, vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, and dementia. Using human positional cloning and crosses with spontaneous mouse models, we have identified the gene responsible for this disorder. First, we used a 0.1cM mouse genetic linkage map in the region containing m-npc using a series of intersubspecific mouse backcrosses. We next integrated the murine genetic map with the human genetic and physical maps using cloned DNA fragments generated from the contig of human DNA containing the NP-C gene. Finally we evaluated genes as candidates for NP-C from a pool of cDNA clones and trapped exon fragments isolated from the human physical contig. Using Northern blot, Southern blot, SSCP and sequencing analyses using samples isolated from spontaneous mouse mutants in comparison to their isogenic wild type controls we found that one gene, NPC1 has a retrotransposon insertion resulting in a loss-of-function of the normal gene product in mutant mice. We have also found mutations in human individuals with NPC. We have also established a natural history study in order to determine the timecourse of disease prevention and as a basis for therapeutic interventions. We are using antisense approaches to mimic animal models of this disease to assess therapeutic interventions. We are assessing changes in gene expression to identify potential biomarkers and exploring screens to identify potential interventions.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Human Genome Research Institute
Zip Code
Ory, Daniel S; Ottinger, Elizabeth A; Farhat, Nicole Yanjanin et al. (2017) Intrathecal 2-hydroxypropyl-?-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial. Lancet :
Chandler, Randy J; Williams, Ian M; Gibson, Alana L et al. (2017) Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1. Hum Mol Genet 26:52-64
Nicoli, Elena-Raluca; Al Eisa, Nada; Cluzeau, Celine V M et al. (2016) Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease. PLoS One 11:e0152007
Westbroek, Wendy; Nguyen, Matthew; Siebert, Marina et al. (2016) A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease. Dis Model Mech 9:769-78
Francis, Kevin R; Ton, Amy N; Xin, Yao et al. (2016) Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/?-catenin defects in neuronal cholesterol synthesis phenotypes. Nat Med 22:388-96
Yapici, Nazmiye B; Bi, Yue; Li, Pengfei et al. (2015) Highly stable and sensitive fluorescent probes (LysoProbes) for lysosomal labeling and tracking. Sci Rep 5:8576
Efthymiou, Anastasia G; Steiner, Joe; Pavan, William J et al. (2015) Rescue of an in vitro neuron phenotype identified in Niemann-Pick disease, type C1 induced pluripotent stem cell-derived neurons by modulating the WNT pathway and calcium signaling. Stem Cells Transl Med 4:230-8
Chen, Xin; Bi, Yue; Wang, Tianyang et al. (2015) Lysosomal targeting with stable and sensitive fluorescent probes (Superior LysoProbes): applications for lysosome labeling and tracking during apoptosis. Sci Rep 5:9004
Ottinger, Elizabeth A; Kao, Mark L; Carrillo-Carrasco, Nuria et al. (2014) Collaborative development of 2-hydroxypropyl-?-cyclodextrin for the treatment of Niemann-Pick type C1 disease. Curr Top Med Chem 14:330-9
Fu, Rao; Wassif, Christopher A; Yanjanin, Nicole M et al. (2013) Efficacy of N-acetylcysteine in phenotypic suppression of mouse models of Niemann-Pick disease, type C1. Hum Mol Genet 22:3508-23

Showing the most recent 10 out of 16 publications