Lysosomal storage disorders are fatal genetic diseases caused by defects in a wide range of proteins associated with the endosomal-lysosomal system. Niemann-Pick type C (NPC) disease is a cholesterol- glycosphingolipid (GSL) storage disorder caused most commonly by defects in NPC1, a transmembrane protein believed critical In retroehdbcyWtrafficking of substrates from iys6s6mes,'ahd in NPG2, a soluble lysosome protein of unknown function. Absence of either protein causes an essentially identical condition with affected children exhibiting progressive neurological decline beginning at 4-6 years of age and with death occurring in the second decade of life. An important observation in terms of therapy is that affected children most often appear normal at birth and only later, after a threshold of intracellular storage and metabolic disruption has been exceeded, do clinical symptoms develop. This important feature indicates that there isa window of opportunity after birth when therapy aimed at correction of the metabolic defect could potentially rescue cells from their disease fate and thereby ameliorate or prevent brain dysfunction. Therapeutic options for NPC disease, however, are very limited, with enzyme replacement and cell-mediated therapies providing little hope of benefit, particularly for NPC1 deficiency since this protein is not secreted by cells. Even gene therapy will likely only be beneficial to transduced cells again due to the lack of transfer of the NPC1 protein between cells. These clear limitations have driven development of a new therapeutic option - drugs that can limit the build-up of offending substrates in brain and other organs - known as substrate reduction therapy (SRT). An initial approach here was a small molecule inhibitor of GSL synthesis (N-butyldeoxnorjirimycin, Zavesca?) which we pioneered as a therapy for NPC disease. A more recent finding suggests that a naturally occurring compound, the cholesterol-derived neurosteroid known as allopregnanolone (ALLO), has a similar ability to limit lysosomal storage in NPC disease. While the mechanism by which ALLO is able to achieve this effect is unknown, recent findings suggest a critical feature is its ability to act as a ligand for the pregnane X receptor (PXR) and thereby to exerttranscriptional control over numerous genes, including those controlling sterol synthesis. The overall goals of our study are to optimize the administration and efficacy of SRT agents using the NPC mouse models, to test an expanded number of candidate PXR-ligand compounds and determine their effects,on cholesterol and GSL accumulation, and to determine whether.the-use of SRT agents in combination will lead to even greater efficacy in delaying and/or preventing clinical deterioration in NPC disease. In addition to testing therapies of direct and practical relevance to NPC-affected children, these studies will also further explore the linkage between storage of GSLs and cholesterol in NPC disease and their relationship to NPC1 and NPC2 protein function.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Tagle, Danilo A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Schools of Medicine
United States
Zip Code
Boudewyn, Lauren C; Walkley, Steven U (2018) Current concepts in the neuropathogenesis of mucolipidosis type IV. J Neurochem :
Boudewyn, Lauren C; Sikora, Jakub; Kuchar, Ladislav et al. (2017) N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV. Neurobiol Dis 105:257-270
Yang, Dun-Sheng; Stavrides, Philip; Kumar, Asok et al. (2017) Cyclodextrin has conflicting actions on autophagy flux in vivo in brains of normal and Alzheimer model mice. Hum Mol Genet 26:843-859
Walkley, Steven U; Davidson, Cristin D; Jacoby, Jonathan et al. (2016) Fostering collaborative research for rare genetic disease: the example of niemann-pick type C disease. Orphanet J Rare Dis 11:161
Davidson, Cristin D; Fishman, Yonatan I; Puskás, István et al. (2016) Efficacy and ototoxicity of different cyclodextrins in Niemann-Pick C disease. Ann Clin Transl Neurol 3:366-80
Praggastis, Maria; Tortelli, Brett; Zhang, Jessie et al. (2015) A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele. J Neurosci 35:8091-106
Vite, Charles H; Bagel, Jessica H; Swain, Gary P et al. (2015) Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease. Sci Transl Med 7:276ra26
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
Pontikis, Charles C; Davidson, Cristin D; Walkley, Steven U et al. (2013) Cyclodextrin alleviates neuronal storage of cholesterol in Niemann-Pick C disease without evidence of detectable blood-brain barrier permeability. J Inherit Metab Dis 36:491-8
Fan, Martin; Sidhu, Rohini; Fujiwara, Hideji et al. (2013) Identification of Niemann-Pick C1 disease biomarkers through sphingolipid profiling. J Lipid Res 54:2800-14

Showing the most recent 10 out of 17 publications