载脂蛋白模拟纳米盘可减少酸性鞘磷脂酶缺乏症患者的脂质积累并改善肝功能。
Apolipoprotein-mimetic nanodiscs reduce lipid accumulation and improve liver function in acid sphingomyelinase deficiency.
机构信息
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, USA.
Department of Pathology, University of Michigan Medical School, 3510 MSRB1, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109, USA.
出版信息
Nanomedicine. 2023 Sep;53:102705. doi: 10.1016/j.nano.2023.102705. Epub 2023 Aug 24.
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.
酸性鞘磷脂酶缺乏症（ASMD）是一种严重的脂质贮积病，由酸性鞘磷脂酶活性降低引起。ASMD 的特征是鞘磷脂在内体和溶酶体中积累，导致进行性神经功能障碍和肝脾肿大。我们的目的是研究合成载脂蛋白 A-I（ApoA-I）模拟物作为脂质清除剂治疗 ASMD 的效用。我们确定了先导肽 22A 可以剂量依赖性地减少 ASMD 患者皮肤成纤维细胞中鞘磷脂的积累。以合成高密度脂蛋白（sHDL）纳米盘的形式腹腔内给予 22A，可将鞘磷脂从外周组织动员到循环中，并改善 ASMD 小鼠模型的肝功能。总之，我们的数据表明，载脂蛋白模拟物可以作为一种新型的治疗策略，用于调节 ASMD 中观察到的病理变化。
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