Modulation of proteostasis for treatment of Niemann-Pick C disease

2012 Pilot Project Read More


Principal Investigator: Daniel Ory (WashU Medicine)
Co-Investigator: Mark Sands (WashU Medicine)


Niemann-Pick C1 disease is a progressive pediatric neurodegenerative disease for which there are no FDA-approved therapies. Mutations in the Niemann-Pick C1 (NPC1) gene are responsible for most cases of the disease, which is characterized by abnormal accumulation of cholesterol in brain cells. Recent studies have shown that the most prevalent disease causing mutation results in an NPC1 protein that is misfolded and, as a consequence, is rapidly degraded and therefore not delivered to the proper site within the cell. For this pilot project, we will test whether reducing the levels of a cellular quality control protein will increase the levels of the mutant NPC1 protein, reduce cholesterol storage, and improve brain cell function. These experiments will be performed in a new genetically engineered mouse developed at Washington University that expresses the NPC1 mutation that causes human disease. Information learned from these studies may lead to development of treatments for this devastating disease.

Grants and Awards

“A Phase 1 Dose Escalation Study of Vorinostat in Niemann-Pick C1 Disease”
NIH/NICHD U01HD079065-01 (PI, Ory)
The goal of this study is to develop a Phase 1, first-in-human, open-label, single-center, dose escalation study of Vorinostat in late adolescents and adults with NPC1 disease to establish the safety of Vorinostat for treatment of this disorder.

“Proteostatic regulation for treatment of NPC1 disease”
Ara Parseghian Medical Research Fund (PIs, Ory, Maxfield, Walkley)

“Proteostatic regulation for treatment of NPC1 disease”
Harrington Discovery Institute (PI, Ory)


Praggastis M, Tortelli B, Zhang J, Fujiwara H, Sidhu R, Chacko A, Chen Z, Lieberman AP, Davidson C, Walkley SU, Pipalia NH, Maxfield FR, Schaffer JE, and Ory DS. A murine Niemann-Pick C1 (NPC1) I1061T knockin model recapitulates the pathological features of the most prevalent human disease allele. J Neuroscience,  35:8091-8106, (2015).

Ebrahimi-Fakhari D, Wahlster L, Bartz F, Wehrenbeck-Ueding J, Praggastis M, Zhang J, Joggerst-Thomalla B, Theiss S, Grimm D, Ory DS, and Runz H. Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-Pick type C1 disease cells. Hum Mol Genet 25 (16): 3588-3599, (2016).

Chung C, Puthanveetil P, Ory DS, and Lieberman AP. Genetic and pharmacological evidence implicate cathespsin in Niemann-Pick C cerebellar degeneration. Hum Mol Genet  25:1434-46, (2016).

Updated January 2019

Hope Center Investigators

Daniel Ory

Mark Sands


This pilot project is made possible by the Danforth Foundation Challenge.

Danforth Challenge