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Abstract
BackgroundNiemann–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).MethodsHere we design, optimize, and define the mechanism of action of synthetic HDL (sHDL) nanoparticles.ResultsWe 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.ConclusionsTogether, our data establish that sHDL nanoparticles are a potential new therapeutic avenue for Niemann–Pick diseases.
Highlights
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 show that 5A-SM synthetic HDL (sHDL) are non-toxic and effective at reducing cholesterol storage in Niemann–Pick C patient fibroblasts and brain slice cultures from Npc1 mutant mice
Using phospholipids with differing affinities for cholesterol [33], we developed a panel of sHDLs containing various 5A:lipid formulations, including sphingomyelin (SM), a saturated phospholipid (DMPC, 1,2-dimyristoyl-snglycero-3-phosphocholine), or an unsaturated phospholipid (POPC, 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine)
Summary
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). Recent work has taken advantage of endogenous HDL function for the development of synthetic HDL (sHDL) nanoparticles as potential therapeutics for cardiovascular diseases [8,9,10,11]. These nanoparticles are composed of the HDL protein apolipoprotein A-1 (ApoA1) or ApoA1 mimetic peptides surrounding a lipid bilayer to form 10–12-nm diameter discoidal lipoprotein particles [12, 13]. In clinical trials involving ~ 2000 cardiovascular disease patients, sHDL was safe and welltolerated [10, 11, 18,19,20,21], and a large phase III clinical trial in 17,400 patients is currently ongoing (https://clinicaltrials. gov/ct2/show/NCT03473223)
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