Effect of a semi-synthetic oxysterol drug candidate, Oxy210, on atherosclerosis in a mouse model of NASH

半合成氧甾醇候选药物 Oxy210 对 NASH 小鼠模型动脉粥样硬化的影响

• 批准号: 10474926
• 负责人: FARHAD PARHAMI
• 金额: $ 32.07万
• 依托单位: MAX BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-23 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474926
• 关键词: Address; Adherence; Adverse effects; Agonist; Animal Model; Anti-Inflammatory Agents; Antiatherogenic; Antiinflammatory Effect; Arterial Fatty Streak; Arteries; Atherosclerosis; Benign; Blood Circulation; Blood Vessels; CCL2 gene; CETP gene; California; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Line; Cells; Cessation of life; Cholesterol; Cirrhosis; Collaborations; Crystallization; Deposition; Development; Diabetes Mellitus; Disease; Drug Kinetics; Dyslipidemias; Endothelial Cells; Erinaceidae; Event; Family; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Foam Cells; Functional disorder; Genetic; Hepatic; Human; Hypertension; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Interleukin-6; Intervention; Kupffer Cells; LDL Cholesterol Lipoproteins; Laboratories; Lead; Life Style; Lipids; Lipopolysaccharides; Lipoproteins; Liver; Liver Fibrosis; Liver diseases; Low-Density Lipoproteins; Macrophage Activation; Mediating; Mediator of activation protein; Medicine; Metabolic; Metabolic syndrome; Modification; Molecular Mechanisms of Action; Mus; Myocardial Infarction; Necrosis; Oncology; Oral; Orthopedics; Oxidative Stress; Oxides; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phospholipids; Phosphorylcholine; Plasma; Play; Primary carcinoma of the liver cells; Process; Property; Public Health; Receptor Signaling; Reporting; Risk; Risk Factors; Role; Rupture; Safety; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Smoking; Smooth Muscle Myocytes; Stroke; Study models; T-Lymphocyte; TLR2 gene; TLR4 gene; TNF gene; Testing; Therapeutic; Thrombosis; Toll-like receptors; Toxicology; Transforming Growth Factor beta; Transgenic Organisms; United States; Vascular Diseases; Vascular Endothelial Cell; Vascular Smooth Muscle; analog; apolipoprotein E-3; atherogenesis; base; cell injury; chronic inflammatory disease; combat; cytokine; drug candidate; efficacy evaluation; epidemiology study; glycation; human disease; humanized mouse; hypercholesterolemia; in vivo; inhibitor; liver inflammation; liver injury; macrophage; migration; monocyte; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; oxidation; oxidized low density lipoprotein; pandemic disease; prevent; recruit; response; side effect; therapeutic development; therapy design; therapy development; western diet

ABSTRACT Cardiovascular disease (CVD) remains the leading cause of death in the United States and worldwide. The large majority of CVD-related deaths are the direct result of atherosclerosis and its cardiovascular complications. Atherosclerosis is a chronic inflammatory disease triggered by low density lipoprotein cholesterol (LDL-C), its accumulation and oxidation in the artery wall, and recruitment of macrophages that become foam cells as they try to remove the lipoprotein oxidation products but die in the process before exiting the vascular wall. Despite recent improvements in the management of atherosclerosis, including the use of lipid lowering drugs and promotion of lifestyle changes, the mortality from CVC is expected to increase from over 17 million in 2018 to almost 24 million by 2030 globally. In recent years, in addition to classic risk factors for atherosclerosis, namely diabetes, hypercholesterolemia, hypertension and smoking, a significant correlation between non-alcoholic fatty liver disease (NAFLD) and atherosclerosis has been reported. Patients with NAFLD die from CVD more frequently than from liver disease, and NAFLD and its more severe condition, non-alcoholic steatohepatitis (NASH), are now considered independent, and likely causal, risk factors for the development of atherosclerosis. It has been therefore proposed that therapies that treat NAFLD may also inhibit atherogenesis, especially since these diseases share common underlying factors including inflammation, lipid deposition and oxidation, and dysfunctional macrophages. At MAX BioPharma we have identified a lead proprietary semi-synthetic oxysterol, Oxy210, that significantly inhibits NASH in a humanized mouse model, ApoE*3-Leiden.CETP, as evidenced by reduction in hepatic lipid deposition, inflammation, and fibrosis as well as reduced inflammatory cytokines in the circulation. Oxy210 is orally bioavailable and has favorable pharmacokinetic and safety profiles and is readily scalable. In preliminary studies we have found that Oxy210 has anti-inflammatory effects in macrophages treated with lipopolysaccharide or the atherogenic phospholipid, PGPC, through inhibition of toll-like receptor signaling. We hypothesize that given Oxy210’s inhibitory effects on NASH and inflammation, and given the common mediators of NASH and atherosclerosis, Oxy210 may also possess anti-atherosclerosis properties. In the present application we propose to test this hypothesis in vitro and in vivo through studies outlined in 3 specific Aims: 1) Examination of the effect of Oxy210 on the activation of HSCs, Kupffer cells and vascular endothelial cells treated with LPS or a synthetic TLR2 agonist in vitro; 2) Examination of the molecular mechanisms of action (MoAs) for anti-inflammatory effects of Oxy210 in vitro; and 3) Assessment of the effect of Oxy210 on atherogenesis in ApoE*3-Leiden.CETP transgenic humanized mouse model of NASH in vivo. Findings from the proposed studies will demonstrate the potential of Oxy210 as a first in class drug candidate for therapeutic development for the treatment of NASH and CVD.

抽象的 心血管疾病（CVD）仍然是美国和全世界死亡的主要原因。 绝大多数与CVD相关的死亡是动脉粥样硬化及其心血管并发症的直接结果。 动脉粥样硬化是一种由低密度脂蛋白胆固醇（LDL-C）引发的慢性炎症性疾病，其 动脉壁中的积累和氧化，以及巨噬细胞的募集，这些细胞在它们形成泡沫细胞时 尽管尝试去除脂蛋白氧化产物，但在离开血管壁之前就死亡了。 最近在动脉粥样硬化的治疗方面取得了进展，包括使用降脂药物和 随着生活方式的改变，CVC的死亡率预计将从2018年的1700万以上增加到 到 2030 年，全球将有近 2400 万人。 近年来，除了动脉粥样硬化的经典危险因素外， 糖尿病、高胆固醇血症、高血压与吸烟、非酒精脂肪酸之间存在显着相关性 据报道，肝病 (NAFLD) 和动脉粥样硬化患者死于 CVD 的比例更高。 常见于肝脏疾病、NAFLD 及其更严重的非酒精性脂肪性肝炎 (NASH)，现在被认为是动脉粥样硬化发展的独立且可能的因果危险因素。 因此，有人提出治疗 NAFLD 的疗法也可能抑制动脉粥样硬化形成，特别是自从 这些疾病具有共同的潜在因素，包括炎症、脂质沉积和氧化，并且 在 MAX BioPharma，我们发现了一种领先的专有半合成氧甾醇， Oxy210 在人源化小鼠模型 ApoE*3-Leiden.CETP 中显着抑制 NASH，如 减少肝脏脂质沉积、炎症和纤维化，并减少肝脏中的炎症细胞因子 Oxy210 具有口服生物利用度，具有良好的药代动力学和安全性，并且易于使用。 在初步研究中，我们发现 Oxy210 对巨噬细胞具有抗炎作用。 通过抑制 Toll 样受体，用脂多糖或致动脉粥样硬化磷脂 (PGPC) 进行处理 考虑到 Oxy210 对 NASH 和炎症的抑制作用，我们得出了这一结论。 Oxy210 是 NASH 和动脉粥样硬化的常见介质，也可能具有抗动脉粥样硬化特性。 在本申请中，我们建议通过 3 个具体的研究在体外和体内测试这一假设 目的： 1) 检查Oxy210对HSC、Kupffer细胞和血管内皮细胞活化的影响 体外用 LPS 或合成 TLR2 激动剂处理的细胞 2) 检查分子作用机制； (MoAs) Oxy210 的体外抗炎作用；以及 3) 评估 Oxy210 对 ApoE*3-Leiden.CETP 转基因人源化 NASH 小鼠模型体内动脉粥样硬化的发现。 拟议的研究将证明 Oxy210 作为治疗类首个候选药物的潜力 NASH 和 CVD 治疗的开发。