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

摘要 心血管疾病(CVD)仍然是美国和世界范围内的主要死亡原因。这个 绝大多数与心血管疾病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 动脉壁中的积聚和氧化，以及巨噬细胞的募集，这些巨噬细胞在 试图去除脂蛋白氧化产物，但在离开血管壁之前就会死亡。尽管 最近在动脉粥样硬化管理方面的改进，包括使用降脂药物和 推动生活方式转变，CVC死亡率预计将从2018年的1700多万增加到 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，即 糖尿病、高胆固醇血症、高血压与吸烟、非酒精性脂肪显著相关 肝病(NAFLD)和动脉粥样硬化已有报道。非酒精性脂肪肝患者死于心血管疾病的人数更多 常见于肝病、NAFLD及其病情较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的、可能是因果的危险因素。 因此，有人提出，治疗NAFLD的疗法也可能抑制动脉粥样硬化的形成，特别是在 这些疾病具有共同的潜在因素，包括炎症、脂肪沉积和氧化，以及 功能失调的巨噬细胞。在Max BioPharma，我们已经确定了一种铅专有的半合成氧固醇， Oxy210，在人源化小鼠模型ApoE*3-Leden.CETP中显著抑制NASH，如 减少肝脏脂肪沉积、炎症和纤维化，以及减少炎性细胞因子 发行量。Oxy210是口服生物利用度的，具有良好的药代动力学和安全性，并易于 可扩展。在初步研究中，我们发现Oxy210在巨噬细胞中具有抗炎作用 内毒素或致动脉粥样硬化的磷脂PGPC通过抑制Toll样受体的作用 发信号。我们假设给予Oxy210‘S抑制NASH和炎症的作用，并给出了 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的特性。在……里面 在目前的应用中，我们建议通过3个特定的研究在体外和体内检验这一假说 目的：1)检测Oxy210对HSCs、Kupffer细胞和血管内皮细胞活化的影响 脂多糖或合成的TLR2激动剂处理的细胞；2)分子作用机制的检测 (MOAS)Oxy210的体外抗炎作用；3)Oxy210的体外抗炎作用评价 ApoE*3-Leden.CETP转基因NASH人源化小鼠体内动脉粥样硬化的发生研究结果： 拟议的研究将证明Oxy210作为一类治疗候选药物的潜力 NASH和CVD的治疗进展。

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.