LDL Modification in Diabetic Complications

描述(申请人提供)：这个第二阶段的项目将把治疗糖尿病微血管并发症的新型药理药物GLY-022推进到临床阶段，方法是扩大对链脲佐菌素糖尿病大鼠和STZ糖尿病大鼠以及db/db小鼠的肾脏病变的体内研究，通过评估生物利用度、药代动力学和急性致死性，以及通过完成提交IND(调查性新药)申请所需的里程碑，其中包括用GMP制造的材料制备GMP(良好制造规范)大量药物物质和形式毒性、毒理学、毒代动力学和安全性研究。这个项目的基本原理来自我们的工作，证明了用GLY-022抑制低密度脂蛋白修改对db/db小鼠具有肾脏保护作用，并来自第一阶段SBIR可行性研究的结果，以评估GLY-022是否在使用肾素血管紧张素系统(RAS)抑制剂进行慢性治疗的背景下提供额外的保护。这些数据支持这样一种假设，即GLY-022是一种可行的临床候选药物，可以进一步保护正在接受RAS抑制剂治疗的糖尿病患者的肾滤过功能下降。此外，我们获得了GLY-022可能对糖尿病视网膜病变有益的初步数据，这并不是I期研究的一部分。该项目的第一阶段目标是检查GLY-022和一种血管紧张素转换酶抑制剂(ACEI)单独和联合使用对指定治疗目标和肾脏结构/功能参数的影响，预期这些可行性研究的积极结果将为该化合物的第二阶段项目和临床开发提供强大的推动力。在第一阶段项目里程碑的基础上，我们建议继续进行第二阶段项目，包括进一步研究肾病和视网膜病变的适应症、生物利用度、药代动力学和致命性研究，以及使用完全有效的GMP-Lot GLY-022进行的正式动物毒理学、安全性和遗传毒性研究。影响肾脏和眼睛的并发症是糖尿病患者常见的严重问题，需要创新的预防和治疗策略。这一第二阶段的SBIR项目将进入临床阶段，这是一种新型化合物，可以防止糖尿病中发生的脂蛋白修饰，并有助于这些并发症的发展。

DESCRIPTION (provided by applicant): This Phase II project will advance to the clinical stage the novel pharmacologic agent GLY-022 for microvascular complications of diabetes by expanding in vivo studies on nephropathy to the streptozotocin diabetic rat and on retinopathy in the STZ-diabetic rat and in the db/db mouse, by assessing bioavailability, pharmacokinetics, and acute lethality, and by completing the milestones requisite for submission of an IND (Investigational New Drug) application, which include preparation of a GMP (Good Manufacturing Practice) lot of drug substance and formal toxicity, toxicology, toxicokinetic and safety studies with GMP-manufactured material. The rationale for this project derives from our work demonstrating that inhibiting LDL modification with GLY-022 is reno-protective in db/db mice and from results of the Phase I SBIR feasibility studies to evaluate if GLY-022 confers added protection on a background of chronic treatment with a inhibitor of the RAS (renin angiotensin system). These data support the hypothesis that GLY-022 is a viable clinical candidate for further protection against decline in renal filtration function in patients with diabetes being treated with RAS inhibitors. Additionally, and not anticipated as part of the Phase I studies, we obtained preliminary data suggesting that GLY-022 may be of benefit in diabetic retinopathy. The Phase I goals of this project were to examine effects of GLY-022 and an ACEI (angiotensin converting enzyme inhibitor), alone and in combination, on designated therapeutic targets and renal structure/function parameters, with the anticipation that positive results from these feasibility studies would provide strong impetus to pursue a Phase II project and clinical development of this compound. Based on achievement of the Phase I project milestones, we propose proceeding to the Phase II project which encompasses further studies for nephropathy and retinopathy indications, bioavailability, pharmacokinetic and lethality studies, and formal animal toxicology, safety and genotoxicity studies conducted with a fully validated GMP-lot of GLY-022. Complications affecting the kidneys and eyes are common and serious problems in patients with diabetes, and require innovative strategies for prevention and treatment. This Phase II SBIR project will advance to the clinical stage a novel compound that prevents modifications of lipoproteins that occur in diabetes and that contribute to the development of these complications.