Journal article
Synthetic high-density lipoprotein nanoparticles for the treatment of Niemann-Pick diseases
BMC medicine, Vol.17(1), pp.200-200
11/11/2019
DOI: 10.1186/s12916-019-1423-5
PMCID: PMC6849328
PMID: 31711490
Abstract
Background Niemann-Pick disease type C is a fatal and progressive neurodegenerative disorder characterized by the accumulation of unesterified cholesterol in late endosomes and lysosomes. We sought to develop new therapeutics for this disorder by harnessing the body's endogenous cholesterol scavenging particle, high-density lipoprotein (HDL). Methods Here we design, optimize, and define the mechanism of action of synthetic HDL (sHDL) nanoparticles. Results We demonstrate a dose-dependent rescue of cholesterol storage that is sensitive to sHDL lipid and peptide composition, enabling the identification of compounds with a range of therapeutic potency. Peripheral administration of sHDL to Npc1 I1061T homozygous mice mobilizes cholesterol, reduces serum bilirubin, reduces liver macrophage size, and corrects body weight deficits. Additionally, a single intraventricular injection into adult Npc1 I1061T brains significantly reduces cholesterol storage in Purkinje neurons. Since endogenous HDL is also a carrier of sphingomyelin, we tested the same sHDL formulation in the sphingomyelin storage disease Niemann-Pick type A. Utilizing stimulated Raman scattering microscopy to detect endogenous unlabeled lipids, we show significant rescue of Niemann-Pick type A lipid storage. Conclusions Together, our data establish that sHDL nanoparticles are a potential new therapeutic avenue for Niemann-Pick diseases.
Details
- Title: Subtitle
- Synthetic high-density lipoprotein nanoparticles for the treatment of Niemann-Pick diseases
- Creators
- Mark L. Schultz - University of MichiganMaria Fawaz - University of MichiganRuth D. Azaria - University of MichiganTodd C. Hollon - University of MichiganElaine A. Liu - University of MichiganThaddeus J. Kunkel - University of MichiganTroy A. Halseth - University of MichiganKelsey L. Krus - University of MichiganRan Ming - University of MichiganEmily E. Morin - University of MichiganHayley S. McLoughlin - University of MichiganDavid D. Bushart - University of MichiganHenry L. Paulson - University of MichiganVikram G. Shakkottai - University of MichiganDaniel A. Orringer - University of MichiganAnna S. Schwendeman - University of MichiganAndrew P. Lieberman - University of Michigan
- Resource Type
- Journal article
- Publication Details
- BMC medicine, Vol.17(1), pp.200-200
- DOI
- 10.1186/s12916-019-1423-5
- PMID
- 31711490
- PMCID
- PMC6849328
- NLM abbreviation
- BMC Med
- ISSN
- 1741-7015
- eISSN
- 1741-7015
- Publisher
- Springer Nature
- Number of pages
- 18
- Grant note
- R01NS063967 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) R01 NS063967; T32 NS007222; T32 GM007767; T32 HL125242 / US National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Ara Parseghian Medical Research Foundation American Foundation for Pharmaceutical Education T32GM007315 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) Hope for Marian University of Michigan Protein Folding Diseases Initiative Niemann-Pick Canada T32HL125242 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Language
- English
- Date published
- 11/11/2019
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics
- Record Identifier
- 9984366362102771
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