LDL Modification in Diabetic Complications

描述（由申请人提供）：该II期项目将通过将肾病的体内研究扩展到链脲佐菌素糖尿病大鼠、stz糖尿病大鼠和db/db小鼠的视网膜病变研究，通过评估生物利用度、药代动力学和急性死亡率，以及完成提交IND（研究新药）申请所需的里程碑，将治疗糖尿病微血管并发症的新型药物GLY-022推进到临床阶段。其中包括制剂的GMP（良好生产规范）和正式的毒性，毒理学，毒性动力学和安全性研究GMP生产的材料。该项目的基本原理来源于我们的工作，证明GLY-022抑制LDL修饰在db/db小鼠中具有肾保护作用，以及来自一期SBIR可行性研究的结果，以评估GLY-022是否在使用RAS（肾素血管紧张素系统）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GLY-022是一种可行的临床候选药物，可以进一步保护接受RAS抑制剂治疗的糖尿病患者免受肾滤过功能下降的影响。此外，我们获得的初步数据表明，GLY-022可能对糖尿病视网膜病变有益，而不是预期的I期研究的一部分。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）单独或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期项目里程碑的成就，我们建议继续进行II期项目，其中包括肾病和视网膜病变适应症的进一步研究，生物利用度，药代动力学和致病性研究，以及正式的动物毒理学，安全性和遗传毒性研究，并使用完全验证的gmp批号GLY-022进行。影响肾脏和眼睛的并发症是糖尿病患者常见和严重的问题，需要创新的预防和治疗策略。该II期SBIR项目将推进一种新型化合物的临床阶段，该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.