LDL Modification and Diabetic Renal Dysfunction

描述(由申请人提供)：这一阶段SBIR的目标是确定防止低密度脂蛋白修饰与血管紧张素转换酶(ACE)抑制剂相结合是否在阻止2型糖尿病小鼠模型糖尿病肾病的发展和/或延缓进展方面具有额外的益处。这一应用的基本原理来自于将修饰的低密度脂蛋白与糖尿病肾小球硬化联系起来的证据；肾素-血管紧张素系统(RAS)抑制剂提供的不完善的保护，特别是在2型糖尿病和晚期疾病中；以及我们最近的工作表明，防止低密度脂蛋白修饰的小分子在db/db小鼠中具有肾脏保护作用。值得注意的是，这种化合物(命名为GLY-022)减少了尿白蛋白和IV型胶原的排泄，这是肾脏细胞外基质积聚的标志，防止滤过功能的下降，防止肾组织过度产生转化生长因子-β1蛋白，并恢复db/db小鼠的肾小球肾素。这些发现表明，GLY-022可能在治疗人类糖尿病肾病方面具有治疗作用。由于RAS抑制剂被广泛用于白蛋白排泄增加和/或肾小球滤过功能降低的糖尿病患者，重要的是要证明，在进行漫长而昂贵的新疗法的临床开发之前，任何针对糖尿病肾脏疾病的新的干预策略都会在使用RAS抑制剂的背景下提供额外的好处。该项目第一阶段的具体目的是：a)评价和比较赖诺普利和GLY-022单独及联合应用对糖尿病小鼠糖尿病肾病发生和发展的影响；b)进行剂量效应研究，并确定GLY-022在慢性赖诺普利治疗的同时对糖尿病啮齿动物肾脏结构和功能有意义的作用的最佳剂量范围；以及c)评估在糖尿病病程早期与后期添加GLY-022预防或改善用赖诺普利治疗的糖尿病啮齿动物临床肾病结构/功能变化的能力。这一可行性项目的积极结果将为推进该化合物的第二阶段项目和临床开发提供强大的动力。

DESCRIPTION (provided by applicant): The objective of this Phase I SBIR is to determine whether preventing LDL modification, in combination with an angiotensin converting enzyme (ACE) inhibitor, is of added benefit in arresting the development and/or slowing the progression of diabetic nephropathy in a mouse model of type 2 diabetes. The rationale for this application derives from evidence linking modified LDL to diabetic glomerulosclerosis; the imperfect protection provided by inhibitors of the renin-angiotensin system (RAS), particularly in type 2 diabetes and in later stage disease; and our recent work demonstrating that a small molecule that prevents LDL modification is reno-protective in db/db mice. Notably, this compound (designated GLY-022) lessens urinary excretion of albumin and of collagen IV, a marker of renal extracellular matrix accumulation, protects against reduction in filtration function, prevents renal overproduction of TGF-beta1 protein, and restores glomerular nephrin in db/db mice. These findings suggest that GLY-022 may have a therapeutic role in the treatment of renal disease in human diabetes. Since RAS inhibitors are widely used in diabetic patients with increased albumin excretion and/or decreased glomerular filtration function, it is important to document that any proposed novel intervention strategy for diabetic renal disease confers added benefit on a background of treatment with an RAS inhibitor before lengthy and expensive clinical development of new therapies is undertaken. The specific aims of this Phase I project are to: a) Evaluate and compare the effect of lisinopril and of GLY-022, alone and in combination, on the development and progression of diabetic nephropathy in db/db mice; b) Perform dose response efficacy studies and determine optimum dosing range for meaningful effect of GLY-022, when added to chronic lisinopril therapy, on renal structure and function in diabetic rodents; and c) Assess the ability of GLY-022 added early versus later in the course of diabetes to prevent or ameliorate the structure/function changes of overt nephropathy in diabetic rodents treated with lisinopril. Positive results in this feasibility project will provide strong impetus to pursue a Phase II project and clinical development of this compound.