Reducing Renal TGF-B in Diabetic Glomerulosclerosis

项目描述（由申请人提供）：该项目的目的是开发一种用于预防/治疗糖尿病性肾小球硬化的新型药物。这一应用的基本原理来源于我们在体外和体内的研究，这些研究阐明了非酶化糖化白蛋白在糖尿病肾病发病机制中的重要作用，描述了糖化白蛋白诱导的肾小球细胞外基质生成刺激的分子信使。研究表明，用小分子22CPPA减轻糖化白蛋白的负担，可以减轻db/db小鼠糖尿病肾病的所有结构和功能变化。在高血糖、糖尿病动物中，cppa抑制白蛋白中活性氨基与葡萄糖的缩合，并显著降低血清糖化白蛋白的浓度，导致肾小球TGF-Beta1的过度表达减少，即使在高血糖普遍存在时也能预防肾小球硬化和肾功能不全。基于这些发现，我们提出通过抑制糖尿病患者过量的非酶糖基化来靶向肾小球TGF-Beta1的过度表达是预防糖尿病肾病进展的一种可行的治疗策略，22CPPA是治疗糖尿病这一病态并发症的一种新的临床候选药物。该项目的第一阶段目标是描述22CPPA对治疗靶点的剂量反应谱，并检查其急性致死/毒性。在第一阶段，我们将与一家合同制造商合作生产GMP级22CPPA，这将用于第二阶段进行的正式动物毒理学和药代动力学，以支持人类在临床第一阶段（安全性）和第二阶段（早期疗效）试验中首次暴露于该化合物，这也将在第二阶段项目中进行。动物毒理学将使用与临床试验使用的GMP级22CPPA同一批次进行，其持续时间和剂量应与临床试验相适应。time I期项目的具体目标是：1)进行剂量反应疗效研究，确定有效降低糖尿病啮齿动物肾小球TGF B1和血浆糖化白蛋白的最佳剂量范围；2)进行22CPPA的急性毒性/致死性体内研究；3)与符合最佳产率/最小副作用要求的临床级（GMP制造）22CPPA合同制造商开始工艺开发，同时计划在测试、验证、纯度和稳定性方面进行相关分析开发，以获得适合正式动物毒理学的原料药，以支持在人类受试者中使用，并在二期项目中进行I期和II期临床试验。

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.