Clinical Investigations of Niemann-Pick Disease, type C

Porter, Forbes

Abstract

Niemann-Pick Disease, type C (NPC) is a neurodegenerative disorder due to a defect in intracellular lipid and cholesterol transport. As part of a Bench-to-Bedside initiative, we initiated a clinical protocol focused on identifying and characterizing biomarkers that could be used in a subsequent therapeutic trial. Funding to support a research nurse was provided by both the Ara Parseghian Medical Research Foundation and Danas Angels Research Trust. This protocol was initiated in August 2006, and to date we have enrolled fourtyfour NPC patients. This is the largest cohorts of actively followed patients in this country. While most of the patients are children, the patients range in age from 1 to 52 years. This protocol involves neurological, hearing, ophthalmological, psychiatric and medical evaluations. Blood, urine, and cerebral spinal fluid are being collected for biomarker analysis. Evaluations include magnetic resonance imaging combined with spectroscopy and auditory brainstem responses. We plan to continue to enroll new patients and follow this group over time. This initial observational study was instrumental in laying the foundation for a therapeutic trial that will be initiated in September 2009.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIAHD008824-03
• Application #: 7968743
• Support Year: 3
• Fiscal Year: 2009
• Total Cost: $169,279

Institution

• Name: Eunice Kennedy Shriver National Institute of Child Health & Human Development

Publications

Tseng, Wei-Chia; Loeb, Hannah E; Pei, Wuhong et al. (2018) Modeling Niemann-Pick disease type C1 in zebrafish: a robust platform for in vivo screening of candidate therapeutic compounds. Dis Model Mech 11:

Cougnoux, Antony; Drummond, Rebecca A; Collar, Amanda L et al. (2018) Microglia activation in Niemann-Pick disease, type C1 is amendable to therapeutic intervention. Hum Mol Genet 27:2076-2089

Cougnoux, Antony; Movassaghi, Miyad; Picache, Jaqueline A et al. (2018) Gastrointestinal Tract Pathology in a BALB/c Niemann-Pick Disease Type C1 Null Mouse Model. Dig Dis Sci 63:870-880

Dai, Sheng; Dulcey, Andrés E; Hu, Xin et al. (2017) Methyl-?-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK. Autophagy :1-17

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 390:1758-1768

Newton, Jason; Hait, Nitai C; Maceyka, Michael et al. (2017) FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts. FASEB J 31:1719-1730

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

Höglinger, Doris; Nadler, André; Haberkant, Per et al. (2017) Trifunctional lipid probes for comprehensive studies of single lipid species in living cells. Proc Natl Acad Sci U S A 114:1566-1571

Salman, Alexander; Cougnoux, Antony; Farhat, Nicole et al. (2017) Association of NPC1 variant p.P237S with a pathogenic splice variant in two Niemann-Pick disease type C1 patients. Am J Med Genet A 173:1038-1040

Wassif, Christopher A; Cross, Joanna L; Iben, James et al. (2016) High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets. Genet Med 18:41-8