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 (ASH) 和非酒精性脂肪性肝炎 (NASH) 影响很大 目前，美国和世界范围内的主要未满足的医疗需求包括缺乏方法或方法。 特异性消耗活化 HSC 和毛细血管 LSEC 以及非侵入性的试剂 可视化胶原蛋白形成、HSC 激活和 LSEC 的方法和试剂 我们开发了一种蛋白质候选药物（简称为纤维化肝脏毛细血管化）。 “ProAgio”）在新位点靶向整合素 αvβ3，诱导整合素 αvβ3 表达凋亡 ProAgio 通过一种新机制特异性诱导表达整合素 αvβ3 的细胞凋亡。 通过在  的细胞质结构域招募和激活 caspase 8，细胞具有高效能。 在我们的初步研究中，对携带该病毒的小鼠进行治疗，结果显示出肝纤维化/肝硬化 TAA/酒精CCl4诱导和高脂饮食诱导ProAgio逆转NASH小鼠肝脏 此外，我们还开发了新型蛋白质 MRI 造影剂 (ProCA)。 让我们能够评估纤维化肝脏中的胶原蛋白含量和整合素 αvβ3 阳性 HSC 和 LSEC。 纤维化小鼠的 MR 成像证明了我们开发的造影剂的优越性能 用于对健康细胞进行胶原蛋白和整合素 v3 阳性细胞的初步毒性分析。 小鼠表明，ProAgio 和我们开发的 MRI 造影剂在非常高的浓度下对小鼠没有毒性。 该项目的目标是大力开展 ProAgio 作为药物的临床前验证。 我们将通过三个具体目标来实现我们的目标。 目标 1 是检查 ProAgio 在使用高脂肪饮食逆转肝纤维化方面的有效性 加上多次酗酒和慢性酗酒诱发的 ASH 模型的调查。 ProAgio 在 ASH 小鼠模型中的效果将进一步验证 ProAgio 作为一种 ASH/NASH 治疗药物的目标 2 是监测和验证 ProAgio 对胶原蛋白的影响。 和  使用我们开发的 MRI 造影剂进行 MR 成像的纤维化肝脏中的 HSC。 成像辅助验证不仅将验证 ProAgio 作为 ASH/NASH 的有效性 目标3是临床前的治疗剂，同时也验证药物作用的靶点和机制。 通过毒理学 (TOX) 验证 ProAgio 作为 ASH/NASH 治疗候选药物 我们的研究将为 ASH/NASH 治疗开辟一条新途径。 通过蛋白质设计进行诊断/预后我们研究的成功不仅会开发出新的蛋白质。 治疗肝纤维化/肝硬化的药物，还测试高效的 MRI 造影剂 使我们能够准确、非侵入性地监测纤维化进展和消退 治疗效果的评估预计将填补主要的医疗空白。 并促进制定逆转纤维化的治疗策略并跟踪高危患者。