Peptide mimics of BMP7 for treatment of renal fibrosis and diabetic nephropathy

BMP7 的肽模拟物用于治疗肾纤维化和糖尿病肾病

• 批准号: 8393566
• 负责人: WILLIAM J DOWER
• 金额: $ 21.31万
• 依托单位: MEDIKINE, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393566
• 关键词: Accounting; Activins; Address; Adherence; Affinity; Agonist; Animal Model; Antihypertensive Agents; Bacteriophages; Binding; Cell surface; Chemicals; Chinese Hamster Ovary Cell; Chronic; Chronic Kidney Failure; Clinical; Collection; Complications of Diabetes Mellitus; Databases; Development; Diabetes Mellitus; Diabetic Nephropathy; Dialysis procedure; Disease Progression; Diversity Library; End stage renal failure; Enzyme-Linked Immunosorbent Assay; Extracellular Domain; Fibrosis; Foundations; Funding; Generations; Growth Factor; Growth and Development function; Human; Injury; Kidney; Kidney Failure; Kidney Transplantation; Libraries; Life; Ligand Binding; Ligands; Link; Measures; Medical; Modeling; Patients; Peptide Phage Display Library; Peptides; Pharmaceutical Preparations; Phase; Polysaccharides; Preparation; Process; Production; Property; Proteins; Random Peptide Libraries; Renal Tissue; Renal function; Reporting; Screening procedure; Small Business Innovation Research Grant; Specificity; Technology; Testing; Therapeutic; United States; Work; bone; bone morphogenic protein; connective tissue growth factor; cost; cytokine; design; design and construction; glycemic control; improved; inhibin; member; mimetics; novel; novel therapeutic intervention; protein aminoacid sequence; receptor; scale up

DESCRIPTION (provided by applicant): Medikine will use SBIR funding to develop a novel therapeutic approach for treating diabetic nephropathy (DN) - a major life-threatening complication of diabetes, and the leading cause of chronic kidney disease and kidney failure in the United States. In 2008 DN accounted for 44% of all new cases of kidney failure, and more than 200,000 of these patients were treated with chronic dialysis or kidney transplant. The cost of managing DN is enormous, estimated to be $16.8B in the U.S. in 2004. Treatment options are limited, and consist of a combination of increased adherence to glycemic control measures, and administration of anti-hypertensive agents. While these therapies slow the progression, the disease is often inexorable, leading to end stage renal disease. Therefore, there is a large and growing unmet medical need for more effective therapeutic options to address DN, and to avoid the profound and severely debilitating consequences of kidney failure. Medikine will address this need by developing novel peptide mimics of bone morphogenic protein 7 (BMP7) - a key cytokine in the TNFb superfamily that has the ability to halt, and even reverse, the progression of renal fibrosis, which is the primary cause of kidney failure in DN patients. Damage to renal tissue, such as occurs with diabetes patients, causes an increase in local production of TGFb1, and this in turn initiates and maintains kidney fibrosis. Remarkably, in a variety of animal models of kidney injury, BMP7 treatment was reported to reverse existing structural damage, and to restore renal function. However, the pro-fibrotic effector CTGF binds to BMP7, blocking anti-fibrotic activity, and complicating the development of BMP7 itself as an anti-fibrotic agent. Medikine proposes to overcome CTGF interference by creating small peptide mimics of BMP7 (10 to 20 residues) that are not bound or inhibited by CTGF, are unrelated to peptide sequences present in BMP7, and that will evade this regulatory process to provide a novel anti-fibrotic therapy for DN. In Phase I of this SBIR proposal, we will identify a set of peptide ligands, each of which is highly selective for one of the six receptor subunits that can bind BMP7. This will be done by screening the extracellular domains (ECDs) of these receptors against large, random peptide libraries. Information from the peptide binding SAR will be used to design and construct a set of secondary libraries, each enriched in peptides specific to one of the subunits; and a counter-selective screening technology will be employed to optimize peptide selectivity and affinity for each respective subunit. These subtype-selective ligands will then be chemically dimerized in a number of heteromeric configurations to identify agonists of BMP7 receptors. The Medikine Phase II project will focus on further optimization and characterization of the heterodimeric agonists, testing them in animal models of renal fibrosis, and selecting a candidate for clinical development. PUBLIC HEALTH RELEVANCE: Diabetic nephropathy (DN) is a major life-threatening complication of diabetes, is the leading cause of chronic kidney disease and kidney failure in the United States, and is the leading reason for treating patients with chronic dialysis or kidney transplant. A naturally occurring protein called bone morphogenic protein 7 that has the ability to halt, and even reverse, the kidney damaging effects of DN has recently been discovered, but its potential use as a drug is compromised by other naturally occurring proteins that block its beneficial effect. Medikine will develop a novel peptide mimetic of BMP7 that retains the therapeutic potential of the protein, but will not be blocked by other naturally occurring proteins and therefore will represent a novel therapeutic approach for treating DN.

描述（由申请人提供）：Medikine 将利用 SBIR 资金开发一种治疗糖尿病肾病 (DN) 的新型治疗方法，糖尿病肾病是一种威胁生命的糖尿病主要并发症，也是美国慢性肾病和肾衰竭的主要原因。 2008年，DN占所有新发肾衰竭病例的44%，其中超过200,000名患者接受长期透析或肾移植治疗。管理 DN 的成本巨大，2004 年在美国估计为 $16.8B。治疗选择有限，包括加强坚持血糖控制措施和服用抗高血压药物。虽然这些疗法减缓了进展，但疾病往往是不可避免的，导致终末期肾病。因此，对于更有效的治疗方案来解决 DN 并避免肾衰竭带来的深刻而严重的衰弱后果，存在着巨大且不断增长的未满足的医疗需求。 Medikine 将通过开发骨形态发生蛋白 7 (BMP7) 的新型肽模拟物来满足这一需求。骨形态发生蛋白 7 (BMP7) 是 TNFb 超家族中的一种关键细胞因子，能够阻止甚至逆转肾纤维化的进展，肾纤维化是 DN 患者肾衰竭的主要原因。肾组织损伤（例如糖尿病患者的肾组织损伤）会导致局部 TGFb1 生成增加，进而引发并维持肾纤维化。值得注意的是，在多种动物模型中 据报道，对于肾损伤，BMP7 治疗可以逆转现有的结构损伤，并恢复肾功能。然而，促纤维化效应子 CTGF 与 BMP7 结合，阻断抗纤维化活性，并使 BMP7 本身作为抗纤维化剂的开发复杂化。 Medikine 建议通过创建 BMP7 的小肽模拟物（10 至 20 个残基）来克服 CTGF 干扰，这些小肽模拟物不被 CTGF 结合或抑制，与 BMP7 中存在的肽序列无关，并且将逃避这一调节过程，为 DN 提供一种新型抗纤维化疗法。在该 SBIR 提案的第一阶段，我们将鉴定一组肽配体，每个配体对可结合 BMP7 的六个受体亚基中的一个具有高度选择性。这将通过针对大型随机肽库筛选这些受体的胞外结构域 (ECD) 来完成。来自肽结合 SAR 的信息将用于设计和构建一组二级文库，每个二级文库富含一个亚基特异的肽；将采用反选择性筛选技术来优化肽对每个亚基的选择性和亲和力。然后，这些亚型选择性配体将被化学二聚化成多种异聚构型，以鉴定 BMP7 受体的激动剂。 Medikine II 期项目将重点关注异二聚体激动剂的进一步优化和表征，在肾纤维化动物模型中对其进行测试，并选择用于临床开发的候选药物。 公众健康相关性：糖尿病肾病 (DN) 是糖尿病的一种主要危及生命的并发症，是美国慢性肾病和肾衰竭的主要原因，也是治疗慢性透析或肾移植患者的主要原因。一种称为骨形态发生蛋白 7 的天然蛋白质，能够 最近发现，可以阻止甚至逆转 DN 的肾脏损害作用，但其作为药物的潜在用途受到其他天然存在的蛋白质的影响，这些蛋白质会阻碍其有益作用。 Medikine 将开发一种新型 BMP7 肽模拟物，它保留了该蛋白的治疗潜力，但不会被其他天然存在的蛋白阻断，因此将代表一种治疗 DN 的新治疗方法。