LDL Modification in Diabetic Complications

描述（申请人提供）：该II期项目将通过评估生物利用度、药代动力学和急性致死性，将肾病的体内研究扩展到链脲佐菌素糖尿病大鼠，并将STZ糖尿病大鼠和db/db小鼠的视网膜病变的体内研究扩展到糖尿病微血管并发症的新型药理学药物GLY-022的临床阶段，并完成提交IND（研究性新药）申请所需的里程碑，其中包括GMP（药品生产质量管理规范）原料药批次的制备以及GMP生产材料的正式毒性、毒理学、毒代动力学和安全性研究。该项目的基本原理来自我们的工作，证明用GLY-022抑制LDL修饰在db/db小鼠中具有肾脏保护作用，以及I期SBIR可行性研究的结果，以评估GLY-022是否在用RAS（肾素血管紧张素系统）抑制剂长期治疗的背景下赋予额外的保护作用。这些数据支持以下假设：GLY-022是进一步保护接受RAS抑制剂治疗的糖尿病患者免受肾滤过功能下降的可行临床候选药物。此外，作为I期研究的一部分，我们获得了初步数据，表明GLY-022可能对糖尿病视网膜病变有益。该项目的I期目标是检查GLY-022和ACEI（血管紧张素转换酶抑制剂）单独和联合对指定治疗靶点和肾脏结构/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II期项目和临床开发提供强大的动力。基于I期项目里程碑的实现，我们建议继续进行II期项目，其中包括对肾病和视网膜病变适应症的进一步研究、生物利用度、药代动力学和致死率研究，以及使用完全验证的GMP批次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且严重的问题，需要创新的预防和治疗策略。这个二期SBIR项目将推进到临床阶段的一种新的化合物，防止发生在糖尿病和有助于这些并发症的发展脂蛋白的修改。

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.