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

IF 4.2 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Nanomedicine : nanotechnology, biology, and medicine Pub Date : 2023-09-01 DOI:10.1016/j.nano.2023.102705

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

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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.

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在酸性鞘磷脂酶缺乏症中，模拟载脂蛋白纳米盘可减少脂质积聚并改善肝功能。

酸性鞘磷脂酶缺乏症（ASMD）是一种严重的脂质储存障碍，由酸性鞘磷脂蛋白酶活性降低引起。ASMD的特征是鞘磷脂在晚期内体和溶酶体中积聚，导致进行性神经功能障碍和肝脾肿大。我们的目的是研究设计用作脂质清除剂的合成载脂蛋白A-I（ApoA-I）模拟物在治疗ASMD中的效用。我们确定，先导肽22A可以以剂量依赖的方式减少ASMD患者皮肤成纤维细胞中鞘磷脂的积累。在ASMD小鼠模型中，腹膜内施用配制为合成高密度脂蛋白（sHDL）纳米盘的22A将鞘磷脂从外周组织动员到循环中，并改善肝功能。总之，我们的数据表明，载脂蛋白模拟物可以作为一种新的治疗策略来调节ASMD中观察到的病理。

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来源期刊

Nanomedicine : nanotechnology, biology, and medicine 工程技术-纳米科技

CiteScore

11.10

自引率

0.00%

发文量

133

审稿时长

42 days

期刊介绍： The mission of Nanomedicine: Nanotechnology, Biology, and Medicine (Nanomedicine: NBM) is to promote the emerging interdisciplinary field of nanomedicine. Nanomedicine: NBM is an international, peer-reviewed journal presenting novel, significant, and interdisciplinary theoretical and experimental results related to nanoscience and nanotechnology in the life and health sciences. Content includes basic, translational, and clinical research addressing diagnosis, treatment, monitoring, prediction, and prevention of diseases.