Reducing Renal TGF-B in Diabetic Glomerulosclerosis

减少糖尿病肾小球硬化症中的肾 TGF-B

• 批准号: 6549723
• 负责人: MARGO COHEN
• 金额: $ 10万
• 依托单位: EXOCELL, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6549723
• 关键词: diabetic nephropathy; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; glomerulosclerosis; glycation; hypoglycemic agents; laboratory mouse; laboratory rat; transforming growth factors

DESCRIPTION (provided by applicant): The objective of this project is to develop for clinical use a novel pharmacologic agent for the prevention/treatment of diabetic glomerulosclerosis. The rationale for this application derives from our work encompassing in vitro and in vivo studies that have elucidated the important role of nonenzymatically glycated albumin in the pathogenesis of diabetic nephropathy, delineated molecular messengers responsible for glycated albumin-induced stimulation of glomerular extracellular matrix production, and demonstrated that reducing the burden of glycated albumin with the small molecule designated 22CPPA attenuates all of the structural and functional changes of diabetic kidney disease in the db/db mouse. 22CPPA inhibits the condensation of glucose with reactive amino groups in albumin and significantly lowers serum concentrations of glycated albumin in hyperglycemic, diabetic animals, resulting in a reduction of the glomerular over-expression of TGF-Beta1 and prevention of glomerulosclerosis and renal insufficiency even when hyperglycemia prevails. Based on these findings, we propose that targeting the over-expression of glomerular TGF-Beta1 through inhibiting the excess nonenzymatic glycation of album in diabetes is a viable therapeutic strategy for preventing the progression of diabetic nephropathy and that 22CPPA is a novel clinical candidate for treatment of this morbid complication of diabetes. The Phase I goals of this project are to delineate the dose-response profile of 22CPPA on the therapeutic targets, and to examine its acute lethality/toxicity. During Phase I we will work with a contract manufacturer for manufacture of GMP grade 22CPPA, which will be used for the formal animal toxicology and pharmacokinetics that will be performed in Phase II to support initial exposure of humans to the compound in clinical Phase I (safety) and Phase II (early efficacy) trials that also will be undertaken in the Phase II project. Animal toxicology will be conducted with the same lot of GMP grade 22CPPA that is used in clinical trials arid will be commensurate in duration and dosage with the clinical testing to be performed. The specific Aims of time Phase I project, which will constitute Milestones, are to: 1) Perform dose-response efficacy studies amid determine optimum dosing range for meaningful reduction of glomerular TGF B1 and plasma glycated albumin in diabetic rodents; 2) Conduct in vivo studies of acute toxicity/lethality of 22CPPA; and 3) Begin process development with a contract manufacturer for clinical grade (GMP manufactured) 22CPPA that meets requirements with respect to best yield/minimal side products, and concurrently plan for relevant analytical development amid testing, validation, purity, and stability so as to obtain drug substance that is suitable for formal animal toxicology to support use in human subjects, and for conduct of Phase I arid II clinical trials during the Phase II project. PROPOSED COMMERCIAL APPLICATIONS: This project seeks to develop for clinical use a novel pharmacologic agent for the prevention/treatment of diabetic glomerulosclerosis, and is expected to result in commercialization partnering.

描述（由申请人提供）：该项目的目的是开发用于临床使用的新型药理学剂，以预防/治疗糖尿病性肾小球硬化症。该应用程序的基本原理来自我们的工作，包括体外和体内研究，这些研究阐明了非酶糖化白蛋白在糖尿病肾病的发病机理中的重要作用，这些作用是糖化分子诱导的白蛋白诱导的白蛋白刺激的生产，并散发出了囊肿的生产，并在糖尿病的发病机构的发病机构中进行了研究。指定22cppa的小分子减弱了DB/DB小鼠中糖尿病肾脏疾病的所有结构和功能变化。 22CPPA抑制葡萄糖在白蛋白中与反应性氨基的凝结，并显着降低高血糖，糖尿病动物中血清糖化白蛋白的浓度，从而导致TGF-BETA1的肾小球过表达降低，即使在肾小球疾病和肾脏不足的情况下预防了葡萄糖的过表达，即使预防了肾小球的糖尿病。基于这些发现，我们提出，通过抑制糖尿病中肾小球TGF-BETA1的过度表达，是糖尿病中专辑的过量非酶糖基化，这是一种可预防糖尿病性肾病的进展，并且可以治疗22cppa，是22cppa是一种新型的临床候选者，用于治疗这种病态的糖尿病。该项目的第一阶段目标是描述22CPPA在治疗靶标上的剂量反应概况，并检查其急性致死性/毒性。在第一阶段，我们将与合同制造商合作，用于制造GMP 22CPPA，该制造将用于正式的动物毒理学和药代动力学，这些动物毒理学和药代动力学将在第二阶段进行，以支持在临床I期（安全II期）和II期（早期功效）试验中的初始暴露于该化合物中，该试验也将在该阶段II期II期项目中进行。动物毒理学将使用与临床试验中使用的GMP 22CPPA相同的持续时间和剂量进行的，并进行临床测试。时间I期项目的具体目的（将构成里程碑）是：1）在确定最佳剂量范围内进行剂量反应效果研究，以在糖尿病啮齿动物中有意义地减少肾小球TGF B1和血浆糖化白蛋白； 2）进行22cppa急性毒性/致死性的体内研究； 3）开始从临床等级（制造GMP）22CPPA的合同制造商开始流程开发，该22CPPA符合最佳产量/最小副产品的要求，并同时计划在测试，验证，纯度，纯度和稳定性的测试，验证，纯度和稳定性中，以便获得适用于人类毒理学在人类临床上使用正式毒理学的阶段II阶段II和II阶段II阶段II的毒品。 拟议的商业应用： 该项目旨在开发临床使用一种新型的药理学剂，以预防/治疗糖尿病性肾小球硬化，并有望导致商业化合作伙伴。