Targeting Myosin to Treat Polycystic Kidney Disease

靶向肌球蛋白治疗多囊肾

基本信息

批准号：
10699859
负责人：
Hongxia Fu
金额：
$ 29.83万
依托单位：
PLUREXA LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-12 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10699859
关键词：
ATP phosphohydrolase Affect Animal Model Animals Area Binding Biochemical Biological Assay Biological Availability Cells Chronic Kidney Failure Clinical Trials Cyst Cytoskeleton Data Disease Docking Dose Drug Targeting Epithelial Cells Epithelium Feasibility Studies Fibrosis Fluorescence Future Genetic Goals Human In Vitro Individual Inherited Investigational Drugs Kidney Kidney Failure Life Liquid substance Literature Liver Marketing Mendelian disorder Microfilaments Modeling Motor Mus Myosin ATPase Myosin Type II Nonmuscle Myosin Type IIA Organ Organ failure Organoids PKD2 protein Patients Persons Pharmaceutical Preparations Phase Phenotype Polycystic Kidney Diseases Preclinical Testing Proteins Renal Replacement Therapy Renal tubule structure Role Safety Shapes Specificity Structure Testing Therapeutic Tube Tubular formation Vasopressin Receptor Work analog antagonist blebbistatin blood pressure control cell motility cytotoxicity disease phenotype drug development experimental study human model in silico in vivo inhibitor invention lead optimization loss of function mutation non-muscle myosin novel novel therapeutic intervention pharmacophore polycystic kidney disease 1 protein reconstitution side effect simulation single molecule small molecule targeted agent therapy development tolvaptan

项目摘要

PROJECT SUMMARY The goal of this proposal is to advance a new therapeutic approach targeting myosin for polycystic kidney disease (PKD). PKD is a major life-threatening Mendelian disorder that affects 12,000,000 individuals, representing a market opportunity of ~$1 billion. In PKD, tiny tubules in the kidneys, liver, and other organs gradually expand into fluid-filled cysts, leading to organ failure. PKD is commonly inherited as a loss-of-function mutation in PKD1 or PKD2, encoding polycystin-1 (PC1) or polycystin-2 (PC2), respectively. General treatment involves managing complications of chronic kidney disease, controlling blood pressure, and preparing for renal replacement therapy. Tolvaptan, a vasopressin receptor antagonist, is approved for use in rapidly progressing cases, but its modest efficacy and occasionally severe side effects make it unsuitable for many PKD patients. How cysts form mechanistically remains incompletely understood, which has hampered drug development. Thus a compelling need and market exists for new treatments and targets to slow or reverse PKD. To better model human PKD and develop therapeutic strategies, we have invented PKD1-/- and PKD2-/- human kidney organoids, which undergo PKD-specific cyst formation from tubules, reconstituting the disease phenotype in a petri dish. Organoid studies reveal that PKD cyst formation is highly sensitive to the microenvironment, and that blebbistatin, a myosin II inhibitor, greatly increases cystogenesis. Non-muscle myosin II (NMII), a known target of blebbistatin that confers strength and shape to cells, is strongly expressed in tubular epithelia and redistributed in organoid cysts. Conversely, in preliminary studies, we have discovered a myosin II activator that reduces PKD cystogenesis, suggesting a novel therapeutic strategy. This compound has a well-established safety and bioavailability profile in large animal studies. Based on our preliminary data and the literature, we hypothesize that it directly activates NMII heavy chains to strengthen and stiffen the cytoskeleton of kidney tubules, thus limiting their tendency to deform into cysts. The major goal of this proposal is to demonstrate this mechanism of action as proof of concept for targeted drug development. This will be achieved in independent aims using purified NMII in vitro and in phenotypic human and animal models. Aim #1: Demonstrate that our hit compound activates NMII in assays suitable for drug optimization. Aim #2. Elucidate the targetable function of NMII during PKD cyst formation in organoids and in vivo. Completion of these two aims will connect the dots between our therapeutic hit compound, NMII, and PKD cyst formation from the single molecule to organoid scale, elucidating a novel mechanism of action for treating cystic disease. This will demonstrate proof of concept, further validate the therapeutic hit, and lay the groundwork for deeper drug development efforts in Phase II (lead optimization and pre-clinical testing).

项目摘要该建议的目的是推进针对多囊肾脏肌球蛋白的新治疗方法疾病（PKD）。 PKD是一种危及生命的主要孟德尔疾病，影响了12,000,000人，代表大约10亿美元的市场机会。在PKD中，肾脏，肝脏和其他器官中的微小小管逐渐扩展到充满液体的囊肿，导致器官衰竭。 PKD通常被遗传为功能丧失 PKD1或PKD2中的突变分别编码Polycystin-1（PC1）或Polycystin-2（PC2）。一般治疗涉及管理慢性肾脏疾病的并发症，控制血压以及准备肾脏替代疗法。 Tolvaptan是一种加压素受体拮抗剂，被批准用于快速进展情况，但其适度的功效和偶尔的副作用使其不适合许多PKD患者。囊肿的形式如何机械形成尚不完全理解，这阻碍了药物的发展。因此对于新的治疗方法和靶标的降低或反向PKD的需求和市场存在着迫切的需求和市场。为了更好地建模人类PKD并制定治疗策略，我们发明了PKD1 - / - 和PKD2 - / - 从小管中经历PKD特异性囊肿形成的肾脏器官，重新构成疾病表型在培养皿中。器官研究表明，PKD囊肿的形成对微环境高度敏感，并且肌球蛋白II抑制剂（一种大大增加了囊菌素）。非肌肉肌球蛋白II（NMII），已知的在管状上皮中强烈表达了将强度和形状赋予强度和形状的泡蛋白的靶标的重新分布在器官囊肿中。相反，在初步研究中，我们发现了一个肌球蛋白II激活剂减少PKD囊肿发生，提出一种新型的治疗策略。该化合物具有良好的大型动物研究中的安全性和生物利用度。根据我们的初步数据和文献，我们假设它直接激活NMII重链以增强和加强肾脏的细胞骨架小管，因此限制了它们变形为囊肿的趋势。该提议的主要目标是证明这一点作用机理作为靶向药物开发的概念证明。这将在独立目的是使用纯化的NMII体外和表型人类和动物模型。 AIM＃1：证明我们的HIT化合物在适合优化药物优化的测定中激活NMII。目标＃2。阐明了器官和体内PKD囊肿形成期间NMII的目标功能。这两个目标的完成将连接我们的治疗性命中化合物，NMII和PKD囊肿之间的点从单分子到器官量表的形成，阐明了一种新的作用机理，以治疗囊性疾病。这将证明概念证明，进一步验证治疗命中率，并为第二阶段（铅优化和临床前测试）中更深入的药物开发工作。