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）：

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