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， 标志着过度积累的疤痕形成，取代功能组织。这些条件是诱导的 并且进一步由心血管疾病和高血压恶化。肾瘢痕最终导致 肾脏疾病，治疗选择非常有限且昂贵，如透析和 肾脏移植大量肾病患者进展至需要透析或 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（MMP's）是一种 一类酶，可切割细胞外基质成分和其他生物活性分子， 在肾脏疾病的初始阶段被上调。虽然一些MMPs的上调可以是抗- 虽然MMP-2的活化在肾损伤的早期阶段是促纤维化的，但是已经显示MMP-2的活化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）， 对肾纤维化的治疗作用。然而，游离肽具有较差的生物分布和较高的生物利用度。 清除率和降解率。为了避免这些问题，APP-IP将与生物聚合物药物融合 已知弹性蛋白样多肽（ELP）的递送系统，已知其稳定肽治疗剂以改善其 药代动力学和增强肾靶向。初步数据显示，ELP-APP-IP融合蛋白 抑制MMP-2并在肾脏皮质区积聚。我们的实验室还证明，使用MMP- 2敲除大鼠，MMP-2活性的去除防止了盐敏感性高血压的纤维化形成。的 所提出的研究的目标是：1）开发三种不同大小的ELP-APP-IP蛋白， 靶向肽以鉴定具有最大肾定位和MMP-2抑制活性的肽，和2） 通过将ELP-APP-IP施用至建立的高血压诱导的大鼠模型来确定ELP-APP-IP的功效 肾损伤，以确定其是否预防或逆转肾纤维化、改善肾损伤和改善肾功能。 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.