An MMP-2 Inhibitory Biologic for Treatment of Renal Disease

抽象的。 肾纤维化是所有慢性和进行性肾损害肾病的最终共同途径。 被标记为疤痕形成过多，取代了功能组织。这些条件是诱导出来的 并因心血管疾病和高血压而进一步恶化。肾疤痕最终会导致死亡 国家肾脏疾病，对这种疾病的治疗选择非常有限和昂贵，如透析和 肾移植。进展为需要透析或需要透析的肾病患者数量较多 移植突出了这一领域药物开发的巨大需求。基质金属蛋白酶(MMPs)是一种 裂解细胞外基质成分和其他生物活性分子的一类酶，被发现 在肾脏疾病的初始阶段被上调。尽管一些MMP的上调可能会反 纤维化，基质金属蛋白酶-2的激活在肾脏损伤的早期阶段被证明是促纤维化的。基质金属蛋白酶-2可以处理 促纤维化细胞因子，如转化生长因子β和肿瘤坏死因子α和β到 增强炎症和纤维化。一种选择性的基质金属蛋白酶-2抑制肽(APP-IP)被发现可能具有 抗肾纤维化的疗效观察。然而，游离肽的生物分布较差，且较高。 清除率和降解率。为了绕过这些问题，APP-IP将与一种生物聚合物药物融合 传递系统称为弹性蛋白样多肽(ELP)，已知的稳定多肽疗法以改善其 药物动力学和增强肾脏靶向性。初步数据显示，ELP-APP-IP融合蛋白 抑制基质金属蛋白酶-2，并在肾脏皮质区域积聚。我们的实验室也证明了，使用基质金属氧化物- 2基因敲除大鼠，去除基质金属蛋白酶-2活性可预防盐敏感型高血压纤维化的形成。这个 拟议研究的目标是1)开发三种不同大小的ELP-APP-IP蛋白，无论是否有肾脏 以确定肾脏定位和基质金属蛋白酶-2抑制活性最高的靶向多肽，以及2) ELP-APP-IP对已建立的高血压大鼠模型的疗效 肾脏损伤，以确定它是否预防或逆转肾脏纤维化，改善肾脏损伤和改善肾脏 功能。

Abstract. Renal fibrosis is the final common pathway of all chronic and progressive kidney damage nephropathies and is marked as excessive buildup of scar formation, replacing the functional tissue. These conditions are induced and further exacerbated by cardiovascular diseases and hypertension. Renal scarring eventually leads to end state renal disease, for which there are very limited and expensive therapeutic options such as dialysis and kidney transplant. The high number of patients with kidney disease that progress to requiring dialysis or transplant highlights the great need for drug development in this area. Matrix metalloproteinases (MMP’s) are a class of enzymes that cleave the extracellular matrix components and other bioactive molecules and are found to be upregulated during the initial stages of renal diseases. Although upregulation of some MMPs can be anti- fibrotic, MMP-2 activation has been shown to be pro-fibrotic at early stages of renal injury. MMP-2 can process profibrotic cytokines such as transforming growth factor beta and tumor necrosis factor alpha and beta to enhance inflammation and fibrosis. A selective MMP-2 inhibitory peptide (APP-IP) was discovered that may have therapeutic effects against renal fibrosis. However, free peptides suffer from poor biodistribution and high clearance and degradation rates. To circumvent these issues, APP-IP will be fused with a biopolymer drug delivery system known as elastin like polypeptide (ELP), known to stabilize peptide therapeutics to improve their pharmacokinetics and to enhance renal targeting. Preliminary data show that the ELP-APP-IP fusion protein inhibits MMP-2 and accumulates in the cortical region of the kidney. Our lab has also demonstrated, using MMP- 2 knock out rats, that removal of MMP-2 activity prevents fibrosis formation in salt-sensitive hypertension. The goal of the proposed studies are 1) to develop three different sized ELP-APP-IP proteins with or without a kidney targeting peptide to identify the one with the greatest renal localization and MMP-2 inhibitory activity, and 2) to determine the efficacy of ELP-APP-IP by administering it to a established rat model of hypertension induced renal injury to determine if it prevents or reverses kidney fibrosis, ameliorates renal injury and improves kidney function.