Reducing Renal TGF-B in Diabetic Glomerulosclerosis

减少糖尿病肾小球硬化症中的肾 TGF-B

• 批准号: 6954077
• 负责人: MARGO COHEN
• 金额: $ 25万
• 依托单位: EXOCELL, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954077
• 关键词: clinical research; clinical trial phase I; clinical trial phase II; diabetes mellitus therapy; diabetic nephropathy; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; glomerulosclerosis; glycation; human subject; human therapy evaluation; hypoglycemic agents; laboratory rat; metabolism disorder chemotherapy; patient oriented research; pharmacokinetics; toxicology; transforming growth factors

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.

描述（由申请人提供）：该II期项目将进行动物毒理学和药代动力学，并将启动对22CPPA的临床评估，这是一种预防/治疗糖尿病性肾小球硬化症的新型药理学剂。该项目的基本原理源于我们的工作涵盖体外和体内研究，这些研究确定了：a）Amadori修饰的糖化白蛋白（GA）引起了肾小球细胞生物学的显着变化，这些细胞生物学高度想起了糖尿病肾病的体内特征； b）这些作用类似，但与高葡萄糖浓度诱导的效果独立起作用，并在临床标本中发现的糖化蛋白浓度观察到； c）GA刺激TGF-BETA1及其II型信号受体的肾小球产生，并激活肾小球PKC-beta和ERK； d）22CPPA抑制白蛋白中葡萄糖与反应性氨基的凝结，并显着降低高血糖，糖尿病动物中GA的血清浓度； E）在体内抑制22CPPA对白蛋白的非酶糖基化糖化的体内降低了TGF-BETA1的肾小球过表达，并且即使高血糖预期，也可以防止肾小球硬化和肾脏不足。基于这些发现，我们提出，通过抑制糖尿病中白蛋白的过量非酶糖化剂来靶向肾小球TGF-BETA1的过表达是一种可行的治疗策略，可防止糖尿病性肾小球硬化的进展，并且是22CPPA的糖尿病治疗，可用于治疗这种糖尿病。该项目的第一阶段目标是完成了治疗目标上22CPPA的剂量反应概况，以检查其急性致死性/毒性，并启动过程开发以准备GMP制造该项目的II期临床级化合物。第二阶段项目的具体目的是：1）获得并完整的分析测试程序/验证工艺开发的药物和22CPPA的GMP批次； 2）进行药代动力学和生物分布分析以及3）22CPPA的体外遗传毒理学测试； 4）使用GMP制造的22CPPA进行亚急性/慢性形式的动物毒理学，以支持人类受试者的人类临床第一阶段安全性，代谢和药代动力学研究（4周动物TOX。）和IIA临床IIA（12周动物TOX。）试验； 5）向FDA提交调查新药申请； 6）根据FDA提交并批准的方案，对正常健康人类志愿者（单次剂量和多重剂量的单次上升剂量和多个上升剂量）进行了完整的临床安全研究； 7）根据FDA提交并批准的方案，对目标（糖尿病）人群（糖尿病）人群进行短期IIA临床研究，监测安全性和评估疗效； 8）向潜在的商业化伙伴提供结果。