title: Cholesterol homeostatic responses provide biomarkers for monitoring treatment for the neurodegenerative disease Niemann-Pick C1 (NPC1).
abstract: Niemann-Pick C1 (NPC1) disease is a rare, neurodegenerative lysosomal cholesterol storage disorder, typified by progressive cognitive and motor function impairment. Affected individuals usually succumb to the disease in adolescence. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) has emerged as a promising intervention that reduces lipid storage and prolongs survival in NPC1 disease animal models. A barrier to the development of HP-β-CD and other treatments for NPC disease has been the lack of validated biochemical measures to evaluate efficacy. Here we explored whether cholesterol homeostatic responses resulting from HP-β-CD-mediated redistribution of sequestered lysosomal cholesterol could provide biomarkers to monitor treatment. Upon direct CNS delivery of HP-β-CD, we found increases in plasma 24(S)-HC in two independent NPC1 disease animal models, findings that were confirmed in human NPC1 subjects receiving HP-β-CD. Since circulating 24(S)-HC is almost exclusively CNS-derived, the increase in plasma 24(S)-HC provides a peripheral, non-invasive measure of the CNS effect of HP-β-CD. Our findings suggest that plasma 24(S)-HC, along with the other cholesterol-derived markers examined in this study, can serve as biomarkers that will accelerate development of therapeutics for NPC1 disease.
authors: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors: Brett
authors: B
authors: Tortelli
authors: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors: Hideji
authors: H
authors: Fujiwara
authors: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Jessica H
authors: JH
authors: Bagel
authors: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors: Jessie
authors: J
authors: Zhang
authors: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors: Rohini
authors: R
authors: Sidhu
authors: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors: Xuntian
authors: X
authors: Jiang
authors: Department of Health and Human Services, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development.
authors: Nicole M
authors: NM
authors: Yanjanin
authors: Department of Health and Human Services, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development.
authors: Roopa Kanakatti
authors: RK
authors: Shankar
authors: Department of Health and Human Services, Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD, USA and.
authors: Nuria
authors: N
authors: Carillo-Carasco
authors: Department of Health and Human Services, Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD, USA and.
authors: John
authors: J
authors: Heiss
authors: Therapeutics for Rare and Neglected Diseases (TRND) Program, National Center for Advancing Translational Sciences (NCATS), Bethesda, MD, USA.
authors: Elizabeth
authors: E
authors: Ottinger
authors: Department of Health and Human Services, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development.
authors: Forbes D
authors: FD
authors: Porter
authors: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors: Jean E
authors: JE
authors: Schaffer
authors: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Charles H
authors: CH
authors: Vite
authors: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA, dory@wustl.edu.
authors: Daniel S
authors: DS
authors: Ory
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000293:Adolescent; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002648:Child; D002784:Cholesterol / Q000097:blood*; D004195:Disease Models, Animal; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006706:Homeostasis; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D052556:Niemann-Pick Disease, Type C / Q000097:blood / Q000188:drug therapy*; D055815:Young Adult; D047392:beta-Cyclodextrins / Q000008:administration & dosage*
chemical_list: D015415:Biomarkers; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol