Cyclodextrin for Niemann-Pick Type C1 Disease

Niemann-Pick disease type C1 is a fatal genetic disease characterized by a failure to metabolize and dispose of cholesterol and lipids, causing progressively impaired movement and intellectual function. It strikes in early childhood and is lethal within a decade of diagnosis. There are no therapies for Niemann-Pick disease type C1 approved by the Food and Drug Administration (FDA), but 2-hydroxypropyl-ß-cyclodextrin (HPBCD) appears to reduce the cholesterol and lipid accumulation and prolongs survival in disease animal models.

The goal of this project is to generate the extensive data needed to establish safe, effective dosing for the delivery of HPBCD directly into the central nervous system of Niemann-Pick patients and to test the drug for initial safety, efficacy and biomarker reliability in patients.

Scientific Synopsis

At left, fibroblasts homozygous for mutations in NPC1 demonstrate an increased accumulation of red Lysotracker staining indicative of the storage disease. At right, addition of cyclodextrin rescues this lysosomal storage defect.

At left, fibroblasts homozygous for mutations in NPC1 demonstrate an increased accumulation of red Lysotracker staining indicative of the storage disease. At right, addition of cyclodextrin rescues this lysosomal storage defect.

Niemann-Pick disease type C1 is an autosomal recessive, neurodegenerative disease with a frequency of one in 120,000 live births. Approximately 95 percent of cases are caused by mutations of the NPC1 gene, and the remaining 5 percent are caused by mutations in the NPC2 gene. Mutations that produce defective NPC1 protein, a cholesterol trafficking protein, lead to accumulation of unesterified cholesterol and other lipids in lysosomes. Manifestations of the disease include neonatal jaundice, splenomegaly, ataxia, and progressive neurodegenerative impairment of motor and intellectual function. Most often, the onset of symptoms occurs in early childhood, leading to death within a decade. 

Currently, no therapies have been approved by the FDA for this progressively fatal neurodegenerative disease. The molecule HPBCD has been shown to reduce both cholesterol and sphingolipid storage and to prolong survival in two types of Niemann-Pick type C1 animal models. The goal of this project was to provide the preclinical studies and clinical tools needed to establish safe and effective dosing regimens for treatment of human subjects with HPBCD.

Lead Collaborator

Washington University in St. Louis, Missouri

Daniel Ory, M.D.

Public Health Impact

Currently, there are no FDA-approved therapies for this disease. Miglustat, an inhibitor of glycosphingolipid biosynthesis, is approved outside the United States, but a recent controlled study and a series of case reports suggest limited efficacy in NPC.  There is an unmet medical need to develop safe and more effective treatments that significantly delay the symptoms and extend the lifespan of patients with Niemann-Pick disease type C1.


TRND established an interdisciplinary project team of academic and industrial scientists from nine different organizations and received ongoing input from patient advocacy groups to accomplish the clinical evaluation of HPBCD most efficiently. TRND scientists conducted the animal toxicology studies necessary to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) and helped support biomarker studies. TRND provided regulatory support to achieve clearance of the IND application in November 2012, and first-in-human clinical trials began in January 2013 at the NIH Clinical Center.   Due to the strong preclinical and early clinical data, including the Phase 1 trial, the program was licensed to a company, Vtesse Pharma, and received the FDA’s Breakthrough Therapy Designation. This designation could accelerate approval to provide the first effective treatment for slowing the progress or stabilizing the devastating impacts of NPC in children and adolescents. The Phase 1 trial was concluded successfully, and currently, the drug is being tested in a multicenter, multinational Phase 2b/3 clinical efficacy trial sponsored by Vtesse. This TRND project is now concluded.


Collaborative development of 2-Hydroxypropyl-β-Cyclodextrin for the Treatment of Niemann-Pick Type C1 Disease, Current Topics in Medicinal Chemistry, 2014, 14, 1-10

Cholesterol homeostatic responses provide biomarkers for monitoring treatment for the neurodegenerative disease Niemann–Pick C1 (NPC1)Human Molecular Genetics, June 25, 2014

Development and validation of sensitive LC-MS/MS assays for quantification of HP-β-CD in human plasma and CSF, Journal of Lipid Research, May 27, 2014

Cholesterol Oxidation Products Are Sensitive and Specific Blood-Based Biomarkers for Niemann-Pick C1 DiseaseScience Translational Medicine, Nov. 3, 2010

Related Information

News Release: Experimental Treatment for Niemann-Pick Disease Type C1 Appears Safe, Effective (August 2017)

Web Feature: NIH, Academia and Patient Advocate Collaboration Speeds Niemann-Pick Type C1 Research (March 2017)

News Release: NIH teams With Industry to Develop Treatments for Niemann-Pick Disease Type C (January 2015)

News Release: Leading Life Science Syndicate Commits $25 Million to Series A Funding to Launch Vtesse, Inc., the First Rare Disease Company Spun Out of Cydan Development, Inc. (January 2015)

Web Feature: TRND Research Leads to NIH Trial to Test Drug for Niemann-Pick Type C1 (February 2013)

News Release: NIH Clinical Trial Begins for Treatment of Rare, Fatal Neurological Disorder (January 2013)

News Release: RRD Selected as Development Partner for NIH Therapeutics for Rare and Neglected Diseases Program (January 2011)

From the NIH Clinical Center: NIH Bench to Bedside Award: Cyclodextrin Therapy for Niemann-Pick C1 Disease (2011)