TY - JOUR
T1 - Apolipoprotein-mimetic nanodiscs reduce lipid accumulation and improve liver function in acid sphingomyelinase deficiency
AU - Halseth, Troy A.
AU - Correia, Adele B.
AU - Schultz, Mark L.
AU - Fawaz, Maria V.
AU - Kuiper, Esmée Q.
AU - Kumaran, Preethi
AU - Dorsey, Kristen Hong
AU - Schuchman, Edward H.
AU - Lieberman, Andrew P.
AU - Schwendeman, Anna
N1 - Publisher Copyright:
© 2023
PY - 2023/9
Y1 - 2023/9
N2 - 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.
AB - 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.
KW - Acid sphingomyelinase deficiency
KW - Apolipoprotein mimetics
UR - http://www.scopus.com/inward/record.url?scp=85169503929&partnerID=8YFLogxK
U2 - 10.1016/j.nano.2023.102705
DO - 10.1016/j.nano.2023.102705
M3 - Article
C2 - 37633404
AN - SCOPUS:85169503929
SN - 1549-9634
VL - 53
JO - Nanomedicine: Nanotechnology, Biology, and Medicine
JF - Nanomedicine: Nanotechnology, Biology, and Medicine
M1 - 102705
ER -