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

基本信息

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
项目类别：
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

项目摘要

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将使用SBIR资金来开发一种治疗糖尿病性肾病（DN）的新型治疗方法 - 糖尿病的主要威胁生命并发症，是美国慢性肾脏病和肾衰竭的主要原因。 2008年，DN占所有新肾衰竭病例的44％，其中超过200,000例患者接受了慢性透析或肾脏移植治疗。管理DN的成本巨大，2004年在美国估计为16.8B美元。治疗方案有限，包括对血糖控制措施的依从性增加以及抗高血压药的施用组合。尽管这些疗法降低了进展，但这种疾病通常是不可阻碍的，导致终结肾脏疾病。因此，对于解决DN的更有效治疗方案，越来越多的医疗需求越来越多，并避免了肾脏衰竭的严重衰弱的后果。 Medikine将通过开发骨形态蛋白7（BMP7）的新型肽模拟物（BMP7） - TNFB超家族中的关键细胞因子可以解决这种需求，该肾脏纤维化的能力甚至可以逆转，这是DN患者肾衰竭的主要原因。肾脏组织的损害（例如糖尿病患者发生）会导致TGFB1局部产生的增加，而这又会引发并维持肾脏纤维化。值得注意的是，在各种动物模型中据报道，在肾脏损伤中，BMP7治疗可逆转现有的结构损害，并恢复肾功能。但是，促纤维化效应子CTGF与BMP7结合，阻止抗纤维化活性，并使BMP7本身作为抗纤维化剂的发展变得复杂。 Medikine提议通过创建CTGF未结合或抑制的BMP7（10至20个残基）的小肽模仿（10至20个残基）来克服CTGF干扰，与BMP7中存在的肽序列无关，这将逃避这种调节过程以提供新的抗纤维化治疗DN。在该SBIR提案的第一阶段，我们将确定一组肽配体，每种配体对于可以结合BMP7的六个受体亚基之一具有高度选择性。这将通过筛选这些受体的细胞外域（ECD）对大型，随机的肽文库进行。来自肽结合SAR的信息将用于设计和构建一组辅助文库，每个文库都富含特定于其中一个亚基的肽。并且将采用反选择性筛查技术来优化每个相应亚基的肽选择性和亲和力。然后，这些亚型选择配体将在许多异源构型中化学二聚体，以鉴定BMP7受体的激动剂。 Medikine II期项目将集中于杂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测试它们，并选择临床发育的候选者。公共卫生相关性：糖尿病性肾病（DN）是糖尿病的主要威胁生命并发症，是美国慢性肾脏疾病和肾衰竭的主要原因，并且是治疗慢性糖尿病或肾脏移植患者的主要原因。一种天然存在的蛋白质，称为骨形态蛋白7，具有能力最近发现了DN的肾脏破坏作用，但其作为药物的潜在用途被其他天然存在的蛋白质损害，从而阻止其有益作用。 Medikine将开发出一种新型的BMP7肽，该肽保留该蛋白质的治疗潜力，但不会被其他天然存在的蛋白质阻止，因此将代表一种治疗DN的新型治疗方法。