Reducing Renal TGF-B in Diabetic Glomerulosclerosis

项目描述（由申请人提供）：该二期项目将开展动物毒理学和药代动力学研究，并开展预防/治疗糖尿病肾小球硬化的新型药物22CPPA的临床评价。该项目的基本原理源于我们的工作，包括体外和体内研究，这些研究已经确定：a) amadorii修饰的糖化白蛋白（GA）诱导肾小球细胞生物学的显著改变，这与糖尿病肾病的体内特征高度相似；B)这些效应类似于由高葡萄糖浓度引起的效应，但独立于高葡萄糖浓度而起作用，并与临床标本中发现的糖化蛋白浓度一起观察到；c) GA刺激肾小球tgf - β 1及其II型信号受体的产生，激活肾小球pkc - β和ERK；d) 22CPPA抑制高血糖、糖尿病动物白蛋白中活性氨基与葡萄糖的缩合，显著降低血清GA浓度；e) 22CPPA在体内抑制白蛋白的非酶糖化，降低肾小球tgf - β 1的过度表达，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白蛋白的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在治疗靶点上的剂量反应谱，检查其急性致死/毒性，并启动工艺开发，为临床级化合物的GMP生产做准备，用于该项目的第二阶段部分。二期项目的具体目标是：1)获取并完成工艺开发原料药和22CPPA GMP批号的分析试验程序/验证；2)对22CPPA进行药代动力学和生物分布分析；3)体外遗传毒理学检测；4)使用gmp生产的22CPPA进行亚急性/慢性正式动物毒理学研究，以支持人体临床I期安全性、代谢和药代动力学研究（4周动物毒理）和临床IIA期（12周动物毒理）试验；5)向FDA提交在研新药申请；6)在正常健康人体志愿者中完成I期临床安全性研究（单次上升剂量和多次上升剂量），根据提交并获得FDA批准的方案；7)根据FDA提交和批准的方案，在目标（糖尿病）人群中进行短期IIA期临床研究，监测安全性并使用替代标记物评估疗效；8)向潜在的商业化合作伙伴展示成果。

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.