An MMP-2 Inhibitory Biologic for Treatment of Renal Disease

用于治疗肾脏疾病的 MMP-2 抑制性生物制剂

基本信息

批准号：
10469983
负责人：
Adesanya Abisola Akinleye
金额：
$ 4.04万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469983
关键词：
Address Amyloid beta-Protein Area Biodistribution Biological Biological Assay Biological Response Modifier Therapy Biopolymers Cardiovascular Diseases Cause of Death Cell Adhesion Cells Chimeric Proteins Chronic Chronic Kidney Failure Cicatrix Dahl Hypertensive Rats Data Deposition Diabetes Mellitus Dialysis procedure Dose Drug Delivery Systems Drug Kinetics Elastin End stage renal failure Enzymes Epithelial Cells Excision Extracellular Matrix Family Fibrosis Gastrointestinal Diseases Gelatinase A Gelatinase B Gelatinases Genetic Engineering Goals Growth Factor Half-Life Heart Injuries Histologic Human Hypertension Inflammation Inflammatory Inhibition of Matrix Metalloproteinases Pathway Injury to Kidney Intravenous Kidney Kidney Diseases Kidney Transplantation Knock-out Matrilysin Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Microscopy Modeling Musculoskeletal Myofibroblast Organ Organ failure Outcome Pathologic Pathway interactions Patients Peptide Hydrolases Peptides Pharmaceutical Preparations Pharmacotherapy Phenotype Plasma Process Production Proliferating Proteins Rattus Renal Hypertension Renal Tissue Renal function Safety Stromelysin 1 Syndrome TNF gene Testing Therapeutic Therapeutic Effect Tissue Inhibitor of Metalloproteinases Tissues Toxic effect Transforming Growth Factor beta Transplantation Tropoelastin Tubular formation Tumor Necrosis Factor-Beta United States Up-Regulation Urine Zinc base cardiovascular risk factor cytokine drug development efficacy testing epithelial to mesenchymal transition improved in vitro Assay in vivo inhibitor kidney cell kidney cortex kidney fibrosis kidney preservation liver injury migration novel therapeutics organ injury peptide I peptide drug podocyte polypeptide prevent profibrotic cytokine recruit renal damage renal scarring salt sensitive hypertension synthetic protein tumor necrosis factor precursor wound healing

项目摘要

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.

抽象的。肾纤维化是所有慢性和进行性肾脏损伤肾病和被标记为疤痕形成的过量积聚，取代了功能组织。这些条件是诱导的并因心血管疾病和高血压而进一步加剧。肾脏疤痕最终导致结束状态肾脏疾病，有非常有限且昂贵的治疗选择，例如透析和肾脏移植。肾脏疾病的患者数量高，需要透析或移植突出了该领域对药物开发的巨大需求。基质金属蛋白酶（MMP）是清除细胞外基质成分和其他生物活性分子并发现的酶类在肾脏疾病的初始阶段上调。尽管某些MMP的上调可能是抗纤维化，MMP-2激活已显示在肾脏损伤的早期阶段是纤维化的。 MMP-2可以处理纤维化细胞因子，例如转化生长因子β和肿瘤坏死因子alpha和beta到增强炎症和纤维化。发现有选择性的MMP-2抑制性肽（APP-IP）可能具有针对肾纤维化的治疗作用。但是，自由的胡椒遭受生物分布不良和高的苦难清除和降解率。为了解决这些问题，App-IP将与生物聚合物药物融合递送系统称为弹性蛋白，如多肽（ELP），已知可以稳定肽治疗以改善其药代动力学并增强肾脏靶向。初步数据显示ELP-APP-IP融合蛋白抑制MMP-2并积聚在肾脏的皮质区域。我们的实验室也证明了使用MMP- 2敲出大鼠，去除MMP-2活性可防止盐敏感性高血压中的纤维化形成。这拟议的研究的目标是1）开发带有或没有肾脏的三种不同尺寸的ELP-APP-IP蛋白靶向肽以识别具有最大肾脏定位和MMP-2抑制活性的肽，以及2）通过将ELP-APP-IP施用到已建立的高血压诱导的大鼠模型来确定ELP-APP-IP的效率肾脏损伤确定它是否防止或逆转肾脏纤维化，改善肾脏损伤并改善肾脏功能。