Nanoliposome-based Treatment of Amyloid Protein (AL) Toxicity

基于纳米脂质体的淀粉样蛋白 (AL) 毒性治疗

• 批准号: 8803354
• 负责人: Raymond Quezon Migrino
• 金额: --
• 依托单位: PHOENIX VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803354
• 关键词: Address; Adipose tissue; Affinity; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid Proteins; Amyloidosis; Apoptosis; Apoptotic; Binding; Blood Vessels; Caliber; Cardiolipins; Cells; Charge; Cholesterol; Coupling; Deposition; Development; Disease; Electrostatics; Exposure to; Functional disorder; Future; General Population; Glycoproteins; Goals; Health; Heart; Heart failure; Herbicides; Human; Injury; Kidney; Lecithin; Left; Light; Light-Chain Immunoglobulins; Link; Liver; Malignant Neoplasms; Metabolism; Methods; Microvascular Dysfunction; Molecular Chaperones; Morbidity - disease rate; Organ; Organelles; Oxidative Stress; Parkinson Disease; Patients; Phosphatidic Acid; Phospholipids; Plasma Cell Neoplasm; Plasma Cells; Population; Production; Protective Agents; Proteins; Protocols documentation; Recombinants; Reporting; Research; Role; Smooth Muscle Myocytes; Sphingomyelins; Stem cell transplant; Surface; Technology; Testing; Therapeutic; Tissues; Toxic effect; Variant; Vesicle; Veterans; agent orange; arteriole; base; cell injury; chemotherapy; endothelial dysfunction; improved; in vivo; mortality; nanoliposome; nanoparticle; novel; novel strategies; prevent; primary amyloidosis of light chain type; protective effect; protein misfolding; response; success; sulfated glycoprotein 2; tool

DESCRIPTION (provided by applicant): Amyloid protein-misfolding diseases such as Alzheimer's (AD) and light chain amyloidosis (AL) remain intractable diseases with high morbidity and mortality. In AL, a plasma cell malignancy from clonal overproduction of immunoglobulin light chain proteins (LC) that misfold, and deposit in the heart, vessels and other tissues, median survival is 4 months if left untreated. AL is a malignancy that the VA recognizes as being related to Agent Orange exposure, pointing to its specific relevance in the veteran population. Chemotherapy¿stem cell transplantation, the only treatment available, has high treatment- related mortality and incomplete success rate. We currently lack options to directly treat or protect cells against amyloid protein injury. Amyloid diseases (AL and AD) share common pathophysiology involving oxidative stress and apoptotic injury that occur early in microvessels and tissues exposed to soluble prefibrillar amyloid proteins (now recognized as a major path to injury). Nanoliposomes (NLs) are artificial phospholipid vesicles with a diameter of <100 nm that have great potential for treating amyloid protein disease. Unlike other nanoparticles, NLs are ideal for human treatment because they are non- toxic, non-immunogenic, fully biodegradable and structurally versatile. They can bind amyloid proteins with high affinity in vivo, reducing cell exposure to amyloid proteins. Their surface can be chemically modified to allow tissue targeting and intracellular and even organelle-specific delivery of therapeutic cargo. Among many therapeutic cargos that can be conjugated to NLs, clusterin (also known as apolipoprotein J) has promising potential to protect against amyloid protein cell injury. Clusterin is a constitutively expressed chaperone glycoprotein that has major dual roles of transporting abnormal proteins and is also an important pro-survival protein. It has abnormal metabolism in both AL and AD. Our overall goal is to test nanoliposome-based treatment of amyloid protein disease by developing and testing nanoliposomes alone (unconjugated) or functionalized with clusterin (conjugated) as protective agents against LC-induced toxicity to human vascular tissue. We will test the hypothesis that NLs composed of cholesterol, sphingomyelin (SM), phosphatidylcholine (PC) and phosphatidic acid (PA) will bind LC derived from AL patients thereby reducing toxicity to ex-vivo human adipose arterioles. Second, we will test the hypothesis that NLs functionalized to carry clusterin (both through non-covalent and covalent methods) will allow pericellular and intracellular delivery of clusterin that will also protect against LC injury. To test these hypotheses, in aim 1 we will develop NLs that will efficiently bind LC and quantify NLs' protective effect against LC induced toxicity. In aim 2, we will develop functionalized NLs through conjugation with clusterin for use in intracellular clusterin delivery and test protective effect of conjugated NLs against LC toxicity. In both aims, we will probe key mechanisms underlying the protective effects of NLs. The proposal represents a novel approach to the treatment of amyloid protein disease using nanoparticles that might be useful for the treatment of veterans and patients with AL amyloidosis and other amyloid diseases such as Alzheimer's disease in the future.

描述（由申请人提供）： 淀粉样蛋白蛋白质不满意的疾病，例如阿尔茨海默氏症（AD）和轻链淀粉样变性（AL）仍然具有较高的发病率和死亡率的棘手疾病。在Al中，免疫球蛋白轻链蛋白（LC）的克隆过量产生的等离子体细胞恶性肿瘤，如果未治疗，则中位生存期在心脏，血管和其他组织中，中位生存期为4个月。艾尔是一种恶性肿瘤，即VA认为与橙色橙色的暴露有关，表明其在退伍军人人口中的特定相关性。化学疗法唯一可用的治疗干细胞移植具有高治疗相关的死亡率和不完全的成功率。目前，我们缺乏直接治疗或保护细胞免受淀粉样蛋白损伤的选择。淀粉样蛋白疾病（AL和AD）具有涉及氧化应激和凋亡损伤的常见病理生理学，这些疾病在暴露于固体前纤维纤维淀粉样蛋白的微血管和组织早期发生（现在被公认为是损伤的主要途径）。纳米脂质体（NLS）是人造磷脂蔬菜，直径<100 nm，具有治疗淀粉样蛋白疾病的巨大潜力。与其他纳米颗粒不同，NLS是人类治疗的理想选择，因为它们是无毒的，不发育的，完全可生物降解且在结构上用途广泛的。它们可以在体内结合具有高亲和力的淀粉样蛋白，从而减少细胞暴露于淀粉样蛋白。可以对其表面进行化学修饰，以允许组织靶向，细胞内甚至有细胞器特异性的热货物递送。在许多可以与NLS结合的治疗性兑现中，簇蛋白（也称为载脂蛋白J）已承诺潜在防止淀粉样蛋白蛋白细胞损伤。簇蛋白是一种组成型表达的伴侣糖蛋白，在转运异常蛋白质中具有主要的双重作用，并且也是重要的促生存蛋白。它在AL和AD中都有异常的代谢。我们的总体目的是通过单独开发和测试纳米脂质体（未缀合）或用簇蛋白（共轭）（共轭）作为受保护剂对LC诱导的对人血管组织的毒性的保护剂来测试基于纳米脂体的淀粉样蛋白疾病的治疗。我们将检验以下假设：NLS由胆固醇，鞘磷脂（SM），磷脂酰胆碱（PC）和磷脂酸（PA）组成，将结合源自AL患者的LC，从而降低毒性，从而降低对Ex-Vivo人类脂肪动脉的毒性。其次，我们将检验以下假设：NLS功能化可携带簇蛋白（通过非共价和共价方法）将允许簇簇的细胞周围和细胞内递送，这也将防止LC损伤。为了检验这些假设，在AIM 1中，我们将开发NLS，这些NLS将有效地结合LC并量化NLS对LC诱导毒性的保护作用。在AIM 2中，我们将通过与簇蛋白共轭来开发功能化的NLS，以用于细胞内簇蛋白的递送和测试对LC的共轭NLS的保护作用 毒性。在这两个目标中，我们都将探测NLS受保护作用的基础的关键机制。该提案代表了一种使用纳米颗粒治疗淀粉样蛋白疾病的新方法，该方法可能可用于治疗退伍军人和AL淀粉样变性和其他淀粉样蛋白疾病（例如阿尔茨海默氏病）的患者。

项目成果

Oxidative Stress Alters the Morphology and Toxicity of Aortic Medial Amyloid.

氧化应激改变主动脉内侧淀粉样蛋白的形态和毒性。

• DOI: 10.1016/j.bpj.2015.10.034
• 发表时间: 2015-12-01
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Davies HA;Phelan MM;Wilkinson MC;Migrino RQ;Truran S;Franco DA;Liu LN;Longmore CJ;Madine J
• 通讯作者: Madine J

PEGylated-nanoliposomal clusterin for amyloidogenic light chain-induced endothelial dysfunction.

• DOI: 10.1080/08982104.2016.1274756
• 发表时间: 2018-06
• 期刊: Journal of liposome research
• 影响因子: 4.4
• 作者: Guzman-Villanueva D;Migrino RQ;Truran S;Karamanova N;Franco DA;Burciu C;Senapati S;Nedelkov D;Hari P;Weissig V
• 通讯作者: Weissig V