Reducing Renal TGF-B in Diabetic Glomerulosclerosis

描述（由申请人提供）：本项目的目的是开发一种用于预防/治疗糖尿病肾小球硬化症的新型药物用于临床。本申请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发病机制中的重要作用，描述了负责糖化白蛋白诱导刺激肾小球细胞外基质产生的分子信使，并且证明了用命名为22 CPPA的小分子减少糖化白蛋白的负荷减弱了db/db小鼠中糖尿病肾病的所有结构和功能变化。db小鼠。22 CPPA抑制葡萄糖与白蛋白中活性氨基的缩合，并显著降低高血糖糖尿病动物中糖化白蛋白的血清浓度，从而减少肾小球TGF-β 1的过度表达，并预防肾小球硬化和肾功能不全，即使在高血糖症盛行的情况下。基于这些发现，我们提出，通过抑制糖尿病患者白蛋白的过度非酶糖化来靶向肾小球TGF-β 1的过度表达是预防糖尿病肾病进展的可行治疗策略，并且22 CPPA是治疗糖尿病这种病态并发症的新型临床候选药物。该项目的I期目标是描述22 CPPA对治疗靶点的剂量-反应曲线，并检查其急性致死性/毒性。在第一阶段，我们将与一家合同制造商合作生产GMP级22 CPPA，该产品将用于第二阶段进行的正式动物毒理学和药代动力学研究，以支持人类在第一阶段（安全性）和第二阶段（早期疗效）临床试验中首次暴露于该化合物，该试验也将在第二阶段项目中进行。将使用与临床试验中使用的GMP级22 CPPA相同批次进行动物毒理学研究，并在持续时间和剂量方面与待进行的临床试验相当。I期项目的具体目的是：1）进行剂量-反应有效性研究，确定糖尿病啮齿动物肾小球TGF β 1和血浆糖化白蛋白有意义降低的最佳剂量范围; 2）进行22 CPPA的急性毒性/致死性体内研究;和3）与合同制造商开始临床级工艺开发（GMP生产）22 CPPA符合最佳收率/最少副产物的要求，并同时计划在检测过程中进行相关分析开发，验证、纯度和稳定性，以获得适用于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II期项目期间进行I期和II期临床试验。 拟议的商业应用： 该项目旨在开发用于预防/治疗糖尿病肾小球硬化症的新型药物用于临床，并有望实现商业化合作。

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.