PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

Anna Brown, Siddharth Patel, Carl Ward, Anna Lorenz, Mauren Ortiz, Allison DuRoss, Fabian Wieghardt, Amanda Esch, Elsje G. Otten, Laura Heiser, Viktor I. Korolchuk, Conroy Sun, Sovan Sarkar, Gaurav Sahay

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1-/-) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1-/- cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders.

Original languageEnglish (US)
Article number31750
JournalScientific Reports
Volume6
DOIs
StatePublished - Aug 30 2016

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Type C Niemann-Pick Disease
Micelles
Cholesterol
Lipids
Cyclodextrins
Lysosomes
Autophagy
Poloxamer
Phase III Clinical Trials
Ethylene Glycol
Excipients
Endosomes
Drug Delivery Systems
Liposomes
Neurodegenerative Diseases
Lung
phosphatidylethanolamine

ASJC Scopus subject areas

  • General

Cite this

PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder. / Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; DuRoss, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav.

In: Scientific Reports, Vol. 6, 31750, 30.08.2016.

Research output: Contribution to journalArticle

Brown, A, Patel, S, Ward, C, Lorenz, A, Ortiz, M, DuRoss, A, Wieghardt, F, Esch, A, Otten, EG, Heiser, L, Korolchuk, VI, Sun, C, Sarkar, S & Sahay, G 2016, 'PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder', Scientific Reports, vol. 6, 31750. https://doi.org/10.1038/srep31750
Brown, Anna ; Patel, Siddharth ; Ward, Carl ; Lorenz, Anna ; Ortiz, Mauren ; DuRoss, Allison ; Wieghardt, Fabian ; Esch, Amanda ; Otten, Elsje G. ; Heiser, Laura ; Korolchuk, Viktor I. ; Sun, Conroy ; Sarkar, Sovan ; Sahay, Gaurav. / PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder. In: Scientific Reports. 2016 ; Vol. 6.
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