Pre-clinical Validation of A Novel Protein Drug Candidate for ASH and NASH Treatment

用于 ASH 和 NASH 治疗的新型蛋白质候选药物的临床前验证

• 批准号: 10662418
• 负责人: Jenny J. Yang
• 金额: $ 61.44万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662418
• 关键词: Address; Affect; Alcoholic steatohepatitis; Alcohols; Animals; Binding Sites; Biodistribution; Blood flow; CASP8 gene; Capillarity; Cells; Chronic; Cirrhosis; Clinical Research; Cohort Studies; Collagen; Contrast Media; Cytoplasmic Tail; Development; Diagnosis; Disease; Dose; Drug Kinetics; Effectiveness; Endothelial Cells; Fibrosis; Future; General Population; Goals; Hepatic Stellate Cell; High Fat Diet; Histologic; Induction of Apoptosis; Integrin alphaVbeta3; Integrins; Investigation; Lead; Life; Liver; Liver Fibrosis; Magnetic Resonance Imaging; Medical; Methodology; Methods; Modeling; Monitor; Mus; Organ; Pathogenicity; Patients; Pharmaceutical Preparations; Population; Portal Hypertension; Prognosis; Property; Protein Engineering; Proteins; Rattus; Reagent; Research Project Grants; Resistance; Site; Testing; Tissues; Toxic effect; Toxicology; Validation; Visualization; angiogenesis; antifibrotic treatment; cell type; chronic liver disease; cytotoxic; drug action; drug candidate; effective therapy; effectiveness evaluation; effectiveness validation; follow up assessment; high risk; imaging probe; intrahepatic; invention; liver inflammation; liver injury; liver repair; mouse model; non-invasive monitor; nonalcoholic steatohepatitis; novel; pharmacokinetic model; pre-clinical; preclinical study; recruit; response; success; targeted agent; treatment effect; treatment response; treatment strategy; validation studies

Summary Alcoholic Steatohepatitis (ASH) and Nonalcoholic Steatohepatitis (NASH) affects a large population in US and worldwide. Currently, major unmet medical needs include lack of method or agent to specifically deplete activated HSC and capillarized LSEC as well as noninvasive methodology and reagents to visualize collagen build-up, HSC activation, and LSEC capillarization in fibrotic liver. We have developed a protein drug candidate (referred to as “ProAgio”) that targets integrin αvβ3 at a novel site to induce apoptosis of integrin αvβ3 expressing cells by a novel mechanism. ProAgio specifically induces apoptosis of integrin v3 expressing cells with a high efficacy by recruiting & activating caspase 8 at cytoplasmic domain of. We demonstrated in our preliminary studies that treatment of mice that carries liver fibrosis/cirrhosis induced by TAA/alcohol CCl4 and the high-fat diet induce NASH mice with ProAgio reversed liver fibrosis/cirrhosis. In addition, we have developed novel protein MRI contrast agents (ProCAs) that allow us to assess collagen contents and integrin αvβ3 positive HSCs & LSECs in fibrotic liver. MR imaging of fibrotic mice demonstrated superior properties of our developed contrast agents for collagen and integrin v3 positive cell assessment. Preliminary toxicity analyses with healthy mice indicate that ProAgio and our developed MRI contrast agents are not toxic to mice at very high dose. The goal of this project is to vigorously pre-clinical validation of ProAgio as a drug candidate for ASH/NASH patient treatment. We will achieve our objective by three specific aims. Aim 1 is to examine the effectiveness of ProAgio in reversal of liver fibrosis using high-fat diet plus multiple binge alcohol and chronic alcohol binge induced ASH models. Investigation of the effects of ProAgio in ASH mouse models will further pre-clinical validation of ProAgio as an ASH/NASH treatment drug. Aim 2 is to monitor and validate the effects of ProAgio on collagen and HSC in fibrotic liver by MR imaging using our developed MRI contrast agents. Our MR imaging aided validation will not only validate the effectiveness of ProAgio as an ASH/NASH treatment agent, but also validate the target and mechanism of drug action. Aim 3 is Pre-clinical validations of ProAgio as an ASH/NASH treatment drug candidate via toxicology (TOX) and pharmacokinetic (PK) analyses. Our study will open a new avenue for ASH/NASH treatment and diagnosis/prognosis by protein design. Success in our studies will not only develop a new protein drug for liver fibrosis/cirrhosis treatment but also test highly effective MRI contrast agents that allow us to accurately and non-invasively monitor fibrosis progression and regression for assessment of treatment effects. Such development is expected to fill in the major medical gaps and to facilitate to devise treatment strategy to reverse fibrosis and follow high risk patients.

概括 酒精性脂肪性肝炎（灰）和非酒精性脂肪性肝炎（NASH）影响很大 我们和全球的人口。目前，主要未满足的医疗需求包括缺乏方法或 特定复制活化活化的HSC和毛细血管LSEC以及无创的代理 可视化胶原蛋白堆积，HSC激活和LSEC的方法和试剂 纤维化肝脏中的毛细管化。我们已经开发了一个蛋白质药物（称为 “ proagio”）靶向整合蛋白αVβ3在新的位点诱导整合素αVβ3的凋亡 细胞通过一种新型机制。 proagio特异性诱导整合素v3表达的凋亡 通过在细胞质结构域募集和激活caspase 8，具有高效率的细胞。我们 在我们的初步研究中证明了携带肝纤维化/肝硬化的小鼠的治疗 由TAA/酒精CCL4诱导的，高脂饮食诱导用Proagio逆转肝脏诱导NASH小鼠 纤维化/肝硬化。此外，我们开发了新型的蛋白质MRI对比剂（PROCA） 允许我们评估纤维化肝脏中的胶原蛋白含量和整联蛋白αVβ3阳性HSC和LSEC。 纤维化小鼠的MR成像表现出我们开发的造影剂的出色特性 用于胶原蛋白和整联蛋白V3阳性细胞评估。健康的初步毒性分析 小鼠表明Proagio和我们开发的MRI对比剂在非常对小鼠的毒性中没有毒性 高剂量。该项目的目的是大力对Proagio作为药物进行临时验证 烟灰/纳什患者治疗的候选人。我们将以三个具体目标来实现我们的目标。 AIM 1是检查Proagio使用高脂饮食逆转肝纤维化的有效性 加上多种暴饮暴食和慢性酒精诱发的灰分模型。调查 Proagio在Ash Mouse模型中的影响将进一步对Proagio进行临时验证 灰分/纳什治疗药物。 AIM 2是监视和验证Proagio对胶原蛋白的影响 MR成像使用我们开发的MRI对比剂通过MR成像进行纤维化肝脏中的HSC。我们的MR 成像辅助验证不仅会验证proagio作为灰分/纳什的有效性 治疗剂，但也验证药物作用的靶标和机制。 AIM 3是临床前的 通过毒理学（TOX）和 药代动力学（PK）分析。我们的研究将为灰烬/纳什治疗和 蛋白质设计诊断/预后。在我们的研究中的成功不仅会发展出一种新的蛋白质 用于肝纤维化/肝硬化治疗的药物，但还测试了高效的MRI对比剂， 允许我们准确，非侵入性监测纤维化的进展和回归 评估治疗效果。预计这种发展将填补主要的医疗空白 并促进制定治疗策略以逆转纤维化并跟随高风险患者。