Apolipoprotein-mimetic nanodiscs reduce lipid accumulation and improve liver function in acid sphingomyelinase deficiency

Troy A. Halseth; Adele B. Correia; Mark L. Schultz; Maria V. Fawaz; Esmée Q. Kuiper; Preethi Kumaran; Kristen Hong Dorsey; Edward H. Schuchman; Andrew P. Lieberman; Anna Schwendeman

doi:10.1016/j.nano.2023.102705

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Apolipoprotein-mimetic nanodiscs reduce lipid accumulation and improve liver function in acid sphingomyelinase deficiency

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Apolipoprotein-mimetic nanodiscs reduce lipid accumulation and improve liver function in acid sphingomyelinase deficiency

Troy A. Halseth, Adele B. Correia, Mark L. Schultz, Maria V. Fawaz, Esmée Q. Kuiper, Preethi Kumaran, Kristen Hong Dorsey, Edward H. Schuchman, Andrew P. Lieberman and Anna Schwendeman

Nanomedicine, Vol.53, 102705

09/01/2023

DOI: 10.1016/j.nano.2023.102705

PMCID: PMC10530155

PMID: 37633404

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https://pmc.ncbi.nlm.nih.gov/articles/PMC10530155/pdf/nihms-1928039.pdfView

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Abstract

Acid sphingomyelinase deficiency (ASMD) is a severe lipid storage disorder caused by the diminished activity of the acid sphingomyelinase enzyme. ASMD is characterized by the accumulation of sphingomyelin in late endosomes and lysosomes leading to progressive neurological dysfunction and hepatosplenomegaly. Our objective was to investigate the utility of synthetic apolipoprotein A-I (ApoA-I) mimetics designed to act as lipid scavengers for the treatment of ASMD. We determined the lead peptide, 22A, could reduce sphingomyelin accumulation in ASMD patient skin fibroblasts in a dose dependent manner. Intraperitoneal administration of 22A formulated as a synthetic high-density lipoprotein (sHDL) nanodisc mobilized sphingomyelin from peripheral tissues into circulation and improved liver function in a mouse model of ASMD. Together, our data demonstrates that apolipoprotein mimetics could serve as a novel therapeutic strategy for modulating the pathology observed in ASMD. Synthetic high-density lipoprotein nanodiscs accept excess sphingomyelin from peripheral tissues in a mouse model of ASMD. Created with BioRender.com [Display omitted]

Acid sphingomyelinase deficiency

Apolipoprotein mimetics

Details

Title: Subtitle: Apolipoprotein-mimetic nanodiscs reduce lipid accumulation and improve liver function in acid sphingomyelinase deficiency
Creators: Troy A. Halseth - University of Michigan
Adele B. Correia - University of Michigan
Mark L. Schultz - University of Iowa
Maria V. Fawaz - University of Michigan
Esmée Q. Kuiper - University of Michigan
Preethi Kumaran - University of Michigan
Kristen Hong Dorsey - University of Michigan
Edward H. Schuchman - Icahn School of Medicine at Mount Sinai
Andrew P. Lieberman - University of Michigan
Anna Schwendeman - BioSurfaces (United States)
Resource Type: Journal article
Publication Details: Nanomedicine, Vol.53, 102705
DOI: 10.1016/j.nano.2023.102705
PMID: 37633404
PMCID: PMC10530155
NLM abbreviation: Nanomedicine
ISSN: 1549-9634
eISSN: 1549-9642
Publisher: Elsevier Inc
Language: English
Date published: 09/01/2023
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics
Record Identifier: 9984461801902771

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