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Published in: BMC Medicine 1/2019

Open Access 01-12-2019 | Niemann-Pick Disease | Research article

Synthetic high-density lipoprotein nanoparticles for the treatment of Niemann–Pick diseases

Authors: Mark L. Schultz, Maria V. Fawaz, Ruth D. Azaria, Todd C. Hollon, Elaine A. Liu, Thaddeus J. Kunkel, Troy A. Halseth, Kelsey L. Krus, Ran Ming, Emily E. Morin, Hayley S. McLoughlin, David D. Bushart, Henry L. Paulson, Vikram G. Shakkottai, Daniel A. Orringer, Anna S. Schwendeman, Andrew P. Lieberman

Published in: BMC Medicine | Issue 1/2019

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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.
Appendix
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Metadata
Title
Synthetic high-density lipoprotein nanoparticles for the treatment of Niemann–Pick diseases
Authors
Mark L. Schultz
Maria V. Fawaz
Ruth D. Azaria
Todd C. Hollon
Elaine A. Liu
Thaddeus J. Kunkel
Troy A. Halseth
Kelsey L. Krus
Ran Ming
Emily E. Morin
Hayley S. McLoughlin
David D. Bushart
Henry L. Paulson
Vikram G. Shakkottai
Daniel A. Orringer
Anna S. Schwendeman
Andrew P. Lieberman
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2019
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-019-1423-5

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