BACKGROUND Niemann-Pick disease type C is a fatal and progressive neurodegenerative disorder characterized by the accumulation of unesterified cholesterol in late endosomes and lysosomes. We sought to develop new therapeutics for this disorder by harnessing the body's endogenous cholesterol scavenging particle, high-density lipoprotein (HDL). METHODS Here we design, optimize, and define the mechanism of action of synthetic HDL (sHDL) nanoparticles. RESULTS We demonstrate a dose-dependent rescue of cholesterol storage that is sensitive to sHDL lipid and peptide composition, enabling the identification of compounds with a range of therapeutic potency. Peripheral administration of sHDL to Npc1 I1061T homozygous mice mobilizes cholesterol, reduces serum bilirubin, reduces liver macrophage size, and corrects body weight deficits. Additionally, a single intraventricular injection into adult Npc1 I1061T brains significantly reduces cholesterol storage in Purkinje neurons. Since endogenous HDL is also a carrier of sphingomyelin, we tested the same sHDL formulation in the sphingomyelin storage disease Niemann-Pick type A. Utilizing stimulated Raman scattering microscopy to detect endogenous unlabeled lipids, we show significant rescue of Niemann-Pick type A lipid storage. CONCLUSIONS Together, our data establish that sHDL nanoparticles are a potential new therapeutic avenue for Niemann-Pick diseases.

中文翻译：

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用于治疗尼曼-匹克病的合成高密度脂蛋白纳米颗粒。

背景技术C型尼曼-皮克病是一种致命的进行性神经退行性疾病，其特征在于晚期内体和溶酶体中未酯化胆固醇的积累。我们试图通过利用人体的内源性胆固醇清除颗粒——高密度脂蛋白（HDL）来开发治疗这种疾病的新疗法。方法在这里，我们设计、优化和定义合成 HDL (sHDL) 纳米颗粒的作用机制。结果我们证明了对 sHDL 脂质和肽成分敏感的胆固醇储存的剂量依赖性拯救，从而能够鉴定具有一系列治疗效力的化合物。对 Npc1 I1061T 纯合子小鼠进行外周注射 sHDL 可动员胆固醇，降低血清胆红素，减少肝脏巨噬细胞大小，并纠正体重缺陷。此外，向成人 Npc1 I1061T 大脑进行单次脑室内注射可显着减少浦肯野神经元中的胆固醇储存。由于内源性 HDL 也是鞘磷脂的载体，因此我们在鞘磷脂贮积病 Niemann-Pick A 型中测试了相同的 sHDL 制剂。利用受激拉曼散射显微镜检测内源性未标记脂质，我们显示了对 Niemann-Pick A 型脂质贮积的显着拯救。结论 总之，我们的数据表明 sHDL 纳米粒子是尼曼匹克病的潜在新治疗途径。