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

Publisher: BioMed Central Country of Publication: England NLM ID: 101190723 Publication Model: Electronic Cited Medium: Internet ISSN: 1741-7015 (Electronic) Linking ISSN: 17417015 NLM ISO Abbreviation: BMC Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Lipoproteins, HDL/*therapeutic use ; Niemann-Pick Disease, Type C/*drug therapy; Animals ; Cholesterol/metabolism ; Dose-Response Relationship, Drug ; Female ; Lipids ; Lipoproteins, HDL/chemical synthesis ; Male ; Mice ; Mice, Inbred C57BL ; Nanoparticles/therapeutic use

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.

J Am Heart Assoc. 2015 Aug 25;4(8):e002171. (PMID: 26307570)
Hum Mol Genet. 2010 Mar 1;19(5):837-47. (PMID: 20007718)
Mol Ther Nucleic Acids. 2017 Jun 16;7:200-210. (PMID: 28624196)
J Lipid Res. 2010 Feb;51(2):406-15. (PMID: 19744920)
J Biol Chem. 2008 Mar 28;283(13):8229-36. (PMID: 18216017)
J Lipid Res. 2000 Jun;41(6):1020-6. (PMID: 10828095)
Regul Toxicol Pharmacol. 2018 Dec;100:59-67. (PMID: 30359697)
Biochim Biophys Acta. 2012 Mar;1821(3):396-404. (PMID: 22179027)
J Lipid Res. 2006 Aug;47(8):1700-13. (PMID: 16705213)
Curr Opin Lipidol. 2014 Feb;25(1):40-7. (PMID: 24362356)
JAMA. 2003 Nov 5;290(17):2292-300. (PMID: 14600188)
Nat Rev Drug Discov. 2014 Jun;13(6):445-64. (PMID: 24854407)
J Neurosci. 2013 Nov 13;33(46):18065-79. (PMID: 24227717)
Lab Invest. 1989 Sep;61(3):270-7. (PMID: 2549301)
J Biol Chem. 2001 Nov 23;276(47):43564-9. (PMID: 11559713)
Clin Genet. 2003 Oct;64(4):269-81. (PMID: 12974729)
Curr Opin Lipidol. 2013 Dec;24(6):480-6. (PMID: 24184938)
ACS Nano. 2016 Mar 22;10(3):3015-41. (PMID: 26889958)
J Neurosci. 2016 Jul 27;36(30):8012-25. (PMID: 27466344)
J Pharmacol Exp Ther. 2010 Aug;334(2):634-41. (PMID: 20484557)
J Lipid Res. 2003 Apr;44(4):828-36. (PMID: 12562845)
Nat Biomed Eng. 2017;1:. (PMID: 28955599)
JAMA. 2007 Apr 18;297(15):1675-82. (PMID: 17387133)
J Lipid Res. 2017 Jan;58(1):124-136. (PMID: 27881716)
J Biol Chem. 2003 Aug 29;278(35):32569-77. (PMID: 12813037)
J Lipid Res. 2014 Aug;55(8):1609-21. (PMID: 24664998)
Science. 2008 Dec 19;322(5909):1857-61. (PMID: 19095943)
Neurobiol Dis. 2018 Jul;115:182-193. (PMID: 29660499)
J Lipid Res. 2006 Mar;47(3):622-32. (PMID: 16319418)
Science. 1996 Jan 26;271(5248):518-20. (PMID: 8560269)
Biochim Biophys Acta. 2000 Apr 12;1484(2-3):129-41. (PMID: 10760463)
Hum Mol Genet. 2012 Jul 15;21(14):3205-14. (PMID: 22505584)
J Biol Chem. 2012 Mar 16;287(12):9290-8. (PMID: 22277650)
Expert Rev Cardiovasc Ther. 2008 Oct;6(9):1203-15. (PMID: 18939908)
Eur Heart J. 2014 Dec 7;35(46):3277-86. (PMID: 24780501)
Circ Res. 2010 Jul 23;107(2):217-27. (PMID: 20508181)
J Lipid Res. 2015 Sep;56(9):1727-37. (PMID: 26117661)
Mol Genet Metab. 2017 Jan - Feb;120(1-2):27-33. (PMID: 28164782)
J Med Genet. 1990 Aug;27(8):499-504. (PMID: 2120445)
J Lipid Res. 2007 Oct;48(10):2141-50. (PMID: 17620658)
Neurology. 1992 Dec;42(12):2286-90. (PMID: 1461380)
Prog Lipid Res. 2002 Jan;41(1):66-97. (PMID: 11694269)
Hum Mol Genet. 2018 Apr 15;27(8):1396-1410. (PMID: 29432535)
PLoS One. 2009 Sep 11;4(9):e6951. (PMID: 19750228)
Chem Biol Interact. 2009 Aug 14;180(3):327-39. (PMID: 19426719)
J Neurosci. 2015 May 27;35(21):8091-106. (PMID: 26019327)
Proc Natl Acad Sci U S A. 1975 Aug;72(8):2925-9. (PMID: 241998)
J Biol Chem. 2006 Dec 1;281(48):37081-90. (PMID: 17020879)
Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5477-82. (PMID: 20212119)
Atherosclerosis. 2018 Aug;275:273-295. (PMID: 29980055)
Nat Commun. 2018 Sep 10;9(1):3671. (PMID: 30202070)
Atherosclerosis. 2011 Aug;217(2):395-400. (PMID: 21571275)
Pharmacol Res. 2016 Sep;111:86-99. (PMID: 27155060)
Genes Cells. 2009 Feb;14(2):191-204. (PMID: 19170766)
Biophys J. 1999 Feb;76(2):908-15. (PMID: 9929492)
J Cell Biol. 2010 Feb 22;188(4):547-63. (PMID: 20156964)
Arterioscler Thromb Vasc Biol. 2012 Dec;32(12):2813-20. (PMID: 23152494)
Proc Natl Acad Sci U S A. 1966 Feb;55(2):366-9. (PMID: 5220952)
Nat Rev Mol Cell Biol. 2001 Sep;2(9):657-68. (PMID: 11533723)
Proc Natl Acad Sci U S A. 1985 Dec;82(23):8247-51. (PMID: 3865225)
Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15287-92. (PMID: 18772377)
Acta Neuropathol. 1993;85(2):175-84. (PMID: 8382896)
J Biol Chem. 2004 Apr 9;279(15):15571-8. (PMID: 14747463)
PLoS One. 2010 Nov 29;5(11):e15054. (PMID: 21124786)

T32 GM145304 United States GM NIGMS NIH HHS; T32 HL125242 United States HL NHLBI NIH HHS; R01 NS085054 United States NS NINDS NIH HHS; T32 GM007767 United States GM NIGMS NIH HHS; T32 NS007222 United States NS NINDS NIH HHS; R01 NS063967 United States NS NINDS NIH HHS; T32 GM007315 United States GM NIGMS NIH HHS

Keywords: HDL; NPC1; Niemann–Pick A; Niemann–Pick C; SRS

0 (Lipids)
0 (Lipoproteins, HDL)
97C5T2UQ7J (Cholesterol)

Date Created: 20191113 Date Completed: 20200331 Latest Revision: 20231019

20231215

PMC6849328

10.1186/s12916-019-1423-5

31711490