Reducing Renal TGF-B in Diabetic Glomerulosclerosis

描述(申请人提供)：这个第二阶段的项目将进行动物毒理学和药代动力学研究，并将启动22CPPA的临床评估，22CPPA是一种用于预防/治疗糖尿病肾小球硬化的新型药理学药物。这个项目的基本原理来自我们的体外和体内研究，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变化，这些变化高度相似于糖尿病肾病的体内特征；b)这些影响类似于高糖浓度诱导的影响，但其作用独立于临床标本中发现的糖化蛋白浓度；c)GA刺激肾小球产生转化生长因子-β1及其II型信号受体，并激活肾小球PKC-β和ERK；D)22CPPA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、糖尿病动物的血清GA浓度；e)在体内，22CPPA抑制白蛋白的非酶糖基化，减少肾小球过度表达转化生长因子-β1，并防止肾小球硬化和肾功能不全，即使在高血糖盛行的情况下。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转化生长因子-β1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新的临床候选药物。该项目已完成的第一阶段目标是描绘22CPPA在治疗靶点上的剂量-反应曲线，检查其急性致死性/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。第二阶段项目的具体目标是：1)获得和完成22CPPA工艺开发药物和GMP批次的分析测试程序/验证；2)进行药代动力学和生物分布分析；3)进行22CPPA的体外遗传毒理学测试；4)对GMP制造的22CPPA进行亚急性/慢性正式动物毒理学研究，以支持人类临床第一阶段的安全性、新陈代谢和药代动力学研究(4周动物毒性试验)。临床IIA期(12周动物毒性试验)这些研究包括：1)根据提交给FDA并经FDA批准的方案，在受试者中进行临床试验；5)向FDA提交试验性新药申请；6)根据提交给FDA并得到FDA批准的方案，在正常健康人体志愿者身上完成I期临床安全性研究(单次增加剂量和多次增加剂量)；7)根据提交给FDA并经FDA批准的方案，在目标(糖尿病)人群中进行短期IIA期临床研究，监测替代药物的安全性并评估其疗效；8)根据FDA提交并获得FDA批准的方案，向潜在的商业化合作伙伴呈现结果。

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.