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

描述（由申请人提供）：medicine将使用SBIR资金开发治疗糖尿病肾病（DN）的新治疗方法-糖尿病的主要威胁生命的并发症，也是美国慢性肾脏疾病和肾衰竭的主要原因。2008年，肾病占所有新发肾衰竭病例的44%，其中20多万患者接受了慢性透析或肾移植治疗。管理DN的成本是巨大的，2004年在美国估计为168亿美元。治疗选择是有限的，包括增加对血糖控制措施的坚持和抗高血压药物的使用。虽然这些疗法减缓了病情的进展，但这种疾病往往是不可避免的，导致终末期肾脏疾病。因此，对于更有效的治疗方案来解决DN，并避免肾衰竭的深刻和严重的衰弱后果，存在巨大且不断增长的未满足的医疗需求。mediine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，BMP7是TNFb超家族中的一种关键细胞因子，具有阻止甚至逆转肾纤维化进展的能力，肾纤维化是DN患者肾衰竭的主要原因。肾组织损伤，如糖尿病患者，导致TGFb1的局部产生增加，这反过来启动并维持肾纤维化。值得注意的是，在各种动物模型中

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.