The long term goal of this project is to identify the genetic basis responsible for Niemann-Pick Type C (NP-C) disease, to study its role in the pathogenesis of the disorder and to use this information to aid in the diagnosis and 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. Our group has a long term commitment to studying several aspects of this disease including those involving genetic diagnostic and therapeutic approaches. Through a multi-institute collaboration and a Bench to Bedside award we have established a natural history study in order to determine the time course of disease prevention, identification of biomarkers and as a basis for assessment of therapeutic interventions. Over the last years we have extensively analysed the model model to provide additional insights into the pathogensisi using gene expression analyses. We have been assessing changes in gene expression in the liver and brain to identify pathways that are disrupted. In asymptomatic animals we found changes in genes involving lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, genes involved in apoptosis and oxidative stress appeared to change in late pathological samples. We have also used this analysis to identify potential biomarkers that we then assess inpatient samples. From this we have identified galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1 disease. With NCATs we have initiated a compound screen to identify potential treatment paradigms and have been testing them in vitro and in vivo. We are also using an NIH Directors Challenge award to assist in a whole genome siRNA screen to identify modify loci that contribute to the genetic variation. We are now developing conventional and antisense approaches to mimic animal models of this disease to assess candidate modifier pathways and to assess identified therapeutic interventions.

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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 :
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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

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