Reducing Renal TGF-B in Diabetic Glomerulosclerosis

描述（由申请人提供）：本II期项目将进行动物毒理学和药代动力学研究，并将启动22 CPPA（一种预防/治疗糖尿病肾小球硬化的新型药理学药物）的临床评价。该项目的基本原理来自我们的工作，包括体外和体内研究，这些研究已经确定：a）Amadori修饰的糖化白蛋白（GA）诱导肾小球细胞生物学的显著改变，这高度地使人联想到糖尿病肾病的体内特征; B）这些效应类似于，但独立于，由高葡萄糖浓度诱导的，并在临床样本中发现的糖化蛋白浓度下观察到的那些; c）GA刺激肾小球产生TGF-β 1及其II型信号受体，并激活肾小球PKC-β和ERK; d）22 CPPA抑制葡萄糖与白蛋白中的反应性氨基的缩合，并显著降低高血糖、糖尿病动物中GA的血清浓度;和e）22 CPPA对白蛋白的非酶糖化的体内抑制降低了TGF-β 1的肾小球过表达，并且即使在高血糖症盛行时也防止肾小球硬化和肾功能不全。基于这些研究结果，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小球硬化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。本项目的I期目标（已完成）是描述22 CPPA对治疗靶点的剂量-反应特征，检查其急性致死性/毒性，并启动工艺开发，为本项目II期部分使用的临床级化合物的GMP生产做准备。II期项目的具体目的是：1）获得并完成工艺开发原料药和GMP批次22 CPPA的分析检测程序/验证; 2）进行22 CPPA的药代动力学和生物分布特征分析和3）体外遗传毒理学检测; 4）用GMP制造的22 CPPA进行亚急性/慢性正式动物毒理学以支持人类临床I期安全性，代谢和药代动力学研究（4周动物毒性）和临床IIA期（12周动物毒性）人类受试者试验; 5）向FDA提交研究性新药申请; 6）在正常健康人类志愿者中完成I期临床安全性研究（单次递增剂量和多次递增剂量），根据提交给FDA并获得FDA批准的方案; 7）在目标国家开展短期IIA期临床研究（糖尿病）人群，根据提交给FDA并经FDA批准的方案，监测安全性并评价替代标志物的疗效; 8）向潜在的商业化合作伙伴展示结果。

DESCRIPTION (provided by applicant): This Phase II project will conduct animal toxicology and pharmacokinetics and will initiate clinical evaluation of 22CPPA, a novel pharmacological agent for the prevention/treatment of diabetic glomerulosclerosis. The rationale for this project derives from our work encompassing in vitro and in vivo studies that have established that: a) Amadori-modified glycated albumin (GA) induces significant alterations in glomerular cell biology that are highly reminiscent of the in vivo features of diabetic nephropathy; b) these effects resemble, but operate independent of, those induced by high glucose concentrations and are observed with concentrations of the glycated protein that are found in clinical specimens; c) GA stimulates glomerular production of TGF-beta1 and its type II signaling receptor and activates glomerular PKC-beta and ERK; d) 22CPPA inhibits the condensation of glucose with reactive amino groups in albumin and significantly lowers serum concentrations of GA in hyperglycemic, diabetic animals; and e) in vivo inhibition of the nonenzymatic glycation of albumin by 22CPPA reduces glomerular over-expression of TGF-beta1, and prevents glomerulosclerosis and renal insufficiency even when hyperglycemia prevails. Based on these findings, we have proposed that targeting the over-expression of glomerular TGF-beta1 through inhibiting the excess nonenzymatic glycation of albumin in diabetes is a viable therapeutic strategy for preventing the progression of diabetic glomerulosclerosis and that 22CPPA is a novel clinical candidate for treatment of this morbid complication of diabetes. The Phase I goals of this project, which have been accomplished, were to delineate the dose-response profile of 22CPPA on the therapeutic targets, to examine its acute lethality/toxicity, and to initiate process development in preparation for GMP manufacture of clinical grade compound to be used in the Phase II portions of this project. The Specific Aims of the Phase II project are to: 1) Obtain and complete analytical testing procedures/validation of process developed drug substance and of GMP lot of 22CPPA; 2) Conduct pharmacokinetic and biodistribution profiling and 3) in vitro genetic toxicology testing of 22CPPA; 4) Perform subacute/chronic formal animal toxicology with GMP-manufactured 22CPPA to support human clinical Phase I safety, metabolism and pharmacokinetic studies (4 week animal tox.) and clinical Phase IIA (12 week animal tox.) trials in human subjects; 5) Submit an Investigational New Drug application to the FDA; 6) Complete Phase I clinical safety studies in normal healthy human volunteers (single rising dose and multiple rising dose), according to protocols submitted to and approved by the FDA; 7) Perform short-term Phase IIA clinical studies in target (diabetic) population, monitoring safety and evaluating efficacy with surrogate markers, according to protocols submitted to and approved by the FDA; 8) Present results to prospective commercialization partners.