Department of Pathology, University of Michigan Medical School, 3510 MSRB1, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109, USA.
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA.
BMC Med. 2019 Nov 11;17(1):200. doi: 10.1186/s12916-019-1423-5.
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).
Here we design, optimize, and define the mechanism of action of synthetic HDL (sHDL) nanoparticles.
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.
Together, our data establish that sHDL nanoparticles are a potential new therapeutic avenue for Niemann-Pick diseases.
尼曼-匹克病 C 型是一种致命的进行性神经退行性疾病，其特征是未酯化胆固醇在内体和溶酶体中积累。我们试图通过利用体内内源性胆固醇清除颗粒高密度脂蛋白（HDL）来为这种疾病开发新的治疗方法。
在这里，我们设计、优化并定义了合成高密度脂蛋白（sHDL）纳米颗粒的作用机制。
我们证明了胆固醇储存的剂量依赖性恢复，这种恢复对 sHDL 脂质和肽组成敏感，从而确定了具有一系列治疗效力的化合物。sHDL 对 Npc1 I1061T 纯合子小鼠的外周给药可动员胆固醇，降低血清胆红素，减少肝巨噬细胞大小，并纠正体重不足。此外，单次脑室注射到成年 Npc1 I1061T 大脑中可显著降低浦肯野神经元中的胆固醇储存。由于内源性 HDL 也是神经鞘磷脂的载体，我们在神经鞘磷脂贮积病尼曼-匹克病 A 中测试了相同的 sHDL 配方。利用受激拉曼散射显微镜来检测内源性未标记的脂质，我们显示出尼曼-匹克病 A 脂质储存的显著恢复。
总之，我们的数据表明 sHDL 纳米颗粒是尼曼-匹克病的一种潜在新的治疗方法。
