LDL Modification in Diabetic Complications

糖尿病并发症中的低密度脂蛋白修饰

• 批准号: 7266930
• 负责人: MARGO COHEN
• 金额: $ 112.97万
• 依托单位: EXOCELL, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7266930
• 关键词: Achievement; Acute; Affect; Angiotensin-Converting Enzyme Inhibitors; Animals; Biological Availability; Cardiovascular system; Chemistry; Chronic; Clinical; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Diabetic Retinopathy; Diabetic mouse; Dose; Drug Kinetics; Eye; Feasibility Studies; Filtration; Goals; Investigational Drugs; Investigational New Drug Application; Kidney; Kidney Diseases; Lipoproteins; Low-Density Lipoproteins; Lung; Manufactured Materials; Modification; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Preparation; Prevention strategy; Range; Renin-Angiotensin System; Retinal Diseases; Safety; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Staging; Streptozocin; Structure; Toxic effect; Toxicokinetics; Toxicology; United States Food and Drug Administration; Work; base; computerized data processing; db/db mouse; diabetic rat; genotoxicity; in vivo; inhibitor/antagonist; innovation; novel; prevent; therapeutic target

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.

描述（由申请人提供）：该II期项目将前往临床阶段，新型药理学剂Gly-022，通过扩展体内肾病研究的体内糖尿病性糖尿病性糖尿病大鼠的体内研究，并在db/db/db鼠标中评估链蛋糕性糖尿病性糖尿病大鼠的体内研究，并评估db/db/db鼠标。致死性，并通过完成提交IND（研究性新药）应用所需的里程碑，其中包括准备GMP（良好的制造实践）药物和正式毒性，毒理学，毒理学，毒理学和安全性研究，并使用GMP制造的材料进行安全研究。该项目的基本原理源于我们的工作，表明用GLY-022抑制LDL修饰在DB/DB小鼠中是肾脏保护性的，以及I期SBIR可行性研究的结果，以评估Gly-022的Confliser是否在持续治疗的背景下添加了对RAS抑制剂（肾素敏感素系统的持续治疗）的保护。这些数据支持以下假设：GLY-022是可行的临床候选者，可在用RAS抑制剂治疗的糖尿病患者中进一步保护肾过滤功能下降。此外，作为第一阶段研究的一部分，我们获得了初步数据，这表明GLY-022在糖尿病性视网膜病中可能有益。该项目的第一阶段目标是检查GLY-022和ACEI（血管紧张素转化酶抑制剂），单独和组合，对指定的治疗靶标和肾脏结构/功能参数的影响，并且预期这些可行性研究的积极结果将为II阶段II期计划和临床发展提供强大的影响。根据I阶段项目里程碑的实现，我们提出了II期项目的启动，该项目涵盖了对肾病和视网膜病变适应症，生物可利用度，药代动力学和致死性研究的进一步研究，以及正式的动物毒理学，安全性和遗传毒性研究，该研究通过GMP-lot的GMP-lot of Glot of Glot of Glot-022。影响肾脏和眼睛的并发症是糖尿病患者的常见和严重问题，需要创新的预防和治疗策略。这个II期SBIR项目将促进临床阶段，一种新的化合物，可防止糖尿病中发生的脂蛋白的修饰，并有助于这些并发症的发展。