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伤肾病的最终共同途径 被标记为疤痕形成过度堆积，取代了功能组织。这些条件诱发 心血管疾病和高血压进一步加剧。肾疤痕最终导致结束 国家肾脏疾病，对此的治疗选择非常有限且昂贵，例如透析和 肾移植。大量肾病患者发展到需要透析或 移植凸显了该领域药物开发的巨大需求。基质金属蛋白酶 (MMP) 是 发现了一类可裂解细胞外基质成分和其他生物活性分子的酶 在肾脏疾病的早期阶段表达上调。尽管某些 MMP 的上调可以抗 纤维化，MMP-2 激活已被证明在肾损伤的早期阶段是促纤维化的。 MMP-2可以处理 促纤维化细胞因子，例如转化生长因子β和肿瘤坏死因子α和β 增强炎症和纤维化。发现了一种选择性 MMP-2 抑制肽 (APP-IP)，可能具有 具有抗肾纤维化的治疗作用。然而，游离肽的生物分布差且高 清除率和降解率。为了规避这些问题，APP-IP 将与生物聚合物药物融合 被称为弹性蛋白样多肽（ELP）的递送系统，已知可以稳定肽治疗剂以改善其 药代动力学并增强肾脏靶向。初步数据表明ELP-APP-IP融合蛋白 抑制 MMP-2 并在肾脏皮质区域积聚。我们的实验室还证明，使用 MMP- 2 基因敲除大鼠表明，去除 MMP-2 活性可防止盐敏感性高血压中纤维化的形成。的 拟议研究的目标是 1) 开发三种不同大小的 ELP-APP-IP 蛋白（有或没有肾脏） 靶向肽以确定具有最大肾定位和 MMP-2 抑制活性的肽，以及 2) 通过将 ELP-APP-IP 施用于已建立的高血压大鼠模型来确定 ELP-APP-IP 的功效 肾损伤，以确定是否可以预防或逆转肾纤维化、改善肾损伤并改善肾脏功能 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.