LDL Modification and Diabetic Renal Dysfunction

描述（由申请人提供）：该I期SBIR的目的是确定在2型糖尿病小鼠模型中，预防LDL修饰与血管紧张素转换酶（ACE）抑制剂联合使用是否对阻止糖尿病肾病的发展和/或减缓糖尿病肾病的进展具有额外的益处。这种应用的基本原理来自于将修饰LDL与糖尿病性肾小球硬化联系起来的证据；肾素-血管紧张素系统（RAS）抑制剂提供的保护不完善，特别是在2型糖尿病和晚期疾病中；我们最近的研究表明，一种阻止LDL修饰的小分子在db/db小鼠中具有肾保护作用。值得注意的是，这种化合物（命名为GLY-022）减少尿中白蛋白和IV型胶原蛋白的排泄，IV型胶原蛋白是肾脏细胞外基质积累的标志，防止滤过功能的减少，防止肾脏tgf - β 1蛋白的过量产生，并恢复db/db小鼠的肾小球肾素。这些发现提示GLY-022可能在治疗人类糖尿病肾脏疾病中具有治疗作用。由于RAS抑制剂广泛应用于白蛋白排泄增加和/或肾小球滤过功能下降的糖尿病患者，因此，在进行漫长而昂贵的新疗法临床开发之前，重要的是要证明任何提出的糖尿病肾病的新干预策略都能在使用RAS抑制剂治疗的背景下获得额外的益处。该I期项目的具体目的是：a)评估和比较赖诺普利和GLY-022单独或联合使用对db/db小鼠糖尿病肾病发生和进展的影响；b)进行剂量反应疗效研究，确定GLY-022加入慢性赖诺普利治疗后对糖尿病啮齿动物肾脏结构和功能有意义的最佳剂量范围；c)评估糖尿病早期与晚期添加GLY-022的能力，以预防或改善赖诺普利治疗的糖尿病啮齿动物显性肾病的结构/功能变化。该可行性项目的积极结果将为该化合物的二期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.