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. 2023 Sep:53:102705.
doi: 10.1016/j.nano.2023.102705. Epub 2023 Aug 24.

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

Troy A Halseth  1 , Adele B Correia  2 , Mark L Schultz  3 , Maria V Fawaz  1 , Esmée Q Kuiper  2 , Preethi Kumaran  4 , Kristen Hong Dorsey  4 , Edward H Schuchman  5 , Andrew P Lieberman  2 , Anna Schwendeman  6
Affiliations

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

Troy A Halseth et al. Nanomedicine. 2023 Sep.

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.

Keywords: Acid sphingomyelinase deficiency; Apolipoprotein mimetics.

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Conflict of interest statement

Declaration of competing interest Dr. Schwendeman declares financial interests for board membership, as a paid consultant, for research funding, and/or as equity holder in EVOQ Therapeutics. The University of Michigan has a financial interest in EVOQ Therapeutics, Inc.

Figures

Figure 1:
Figure 1:
Evaluation of apolipoprotein mimetic peptides in vitro. Solubilization of sphingomyelin vesicles during 2-hour incubation with 5mg/mL apolipoprotein mimetic peptides measured by reduction in turbidity at 600nm (A). Sphingomyelin efflux from ASMD fibroblasts after 24-hour treatment with 10μM or 100μM peptide (B). Viability of ASMD patient cells following 24-hour treatment with peptides. (C). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, n.s. not significant. N=3
Figure 2:
Figure 2:
Comparing sHDL to free peptide in vitro. Size distribution of sHDL nanodiscs measured by dynamic light scattering (DLS) (A). Morphology of sHDL nanodiscs observed using negative-stain TEM (B). Sphingomyelin efflux comparison in ASMD skin fibroblasts following 24-hour treatment with free 22A peptide or 22A-DMPC (2:1) sHDL at 10μM peptide concentration (C). Cell viability following 24-hour treatment with free 22A peptide or sHDL at 300μM and 500μM (D). *p<0.05, n.s. not significant. N=3
Figure 3:
Figure 3:
Single dose of sHDL nanodiscs increases circulating levels of sphingomyelin and alters lipoprotein profile in WT and Smpd1−/− mice. Mice were injected I.P. with 100mg/kg of sHDL and serum was analyzed at 2, 6, and 24 hours post-injection for sphingomyelin levels (A). Distribution of lipoproteins in serum for WT and Smpd1−/− mice prior to treatment with sHDL (B), 6 hours after sHDL injection (C), and 24 hours after injection (D) was evaluated using SEC with detection at 265nm. *p<0.05. **p<0.01 compared to initial SM levels. N=3
Figure 4:
Figure 4:
Effects of repeated dosing of sHDL in Smpd1−/− mice. Smpd1−/− or WT mice were given daily injections of saline or 100mg/kg sHDL I.P. for 4 weeks starting at 6 weeks of age. The motor deficits of mice were evaluated via time to traverse a balance beam (A). Livers were weighed at the end of treatment (B). Serum was collected at the end of treatment and analyzed for ALKP (C), AST (D), and ALT (E). N=6-11 mice per group. Error bars are SEM. *p<0.05, **p<0.01
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