MASP-2 Antibodies for Diabetic Neuropathy

描述（由申请方提供）：MASP-2项目的总体目标是开发阻断MASP-2功能的单克隆抗体，以治疗与糖尿病相关的微血管并发症。本申请中提出的工作的目标是验证用于治疗糖尿病性神经病变（DN）的抗MASP-2疗法。糖尿病在发达国家的发病率和患病率不断增加。美国糖尿病协会估计美国有2500万糖尿病患者，每年约有200万新诊断的患者。唯一有效的治疗方法是严格控制血糖水平，尽管即使是最佳实践也不能完全防止高血糖。长期糖尿病经常与微血管并发症有关：约5%的糖尿病患者会发展为严重的糖尿病视网膜病变，可导致失明，而约2%的糖尿病患者会发展为糖尿病肾病并进展为终末期肾病。同时，对于长期糖尿病患者，DN是一种特别使人衰弱的并发症，并且通过使足部易于溃疡和下肢截肢而导致显著的发病率。周围神经功能的逐渐丧失是根本原因。DN患者的管理也是糖尿病相关医疗保健成本的最大贡献者（仅在美国就有50亿至100亿美元）。目前还没有预防DN患者疾病进展的治疗方法。DN的发病机制尚不清楚。慢性低水平血管炎症已成为可能的潜在机制。对患者活检的免疫组织化学研究表明，补体可能发挥作用，补体是一种由组织损伤激活的先天性炎症途径。基于临床研究表明补体凝集素途径在糖尿病肾脏并发症中的疾病修饰作用，我们假设该途径也可能在DN中发挥作用。为了验证这一假设，我们想确定阻断补体凝集素途径是否能预防或治疗DN。这一假设将与伊娃费尔德曼博士和密歇根大学神经病核心实验室（一个AMDCC认证的机构）合作进行测试。针对MASP-2的单克隆抗体将用于此目的，MASP-2是凝集素途径功能所特有和所需的蛋白酶。我们将使用肥胖糖尿病db/db小鼠（一种经验证的DN临床前模型）来确定抗MASP-2抗体治疗是否预防或逆转DN的标志性致病特征，包括感觉功能丧失、神经损伤的电生理学测量和神经纤维丧失的解剖学证据。在该验证的DN模型中成功证明功效将为寻求抗MASP-2抗体用于治疗DN提供令人信服的理由。Omeros目前正在临床前开发一种抗人MASP-2治疗性抗体，可能对患有这种严重的目前无法治疗的疾病的患者有用。 公共卫生相关性：本项目旨在研究MaSniP-2是否能用于预防或治疗疾病。

DESCRIPTION (provided by applicant): The overall objective of the MASP-2 program is to develop a monoclonal antibody that blocks the function of MASP-2, in order to treat microvascular complications associated with diabetes. The goal of the work proposed in this application is to validate anti-MASP-2 therapy for the treatment of diabetic neuropathy (DN). Diabetes mellitus occurs with increasing incidence and prevalence in the developed world. The American Diabetes Association estimates 25 million diabetes patients in the US, with approximately 2 million newly diagnosed patients each year. The only effective treatment is tight control of blood glucose levels, though even best practices provide incomplete protection from hyperglycemia. Long term diabetes is frequently associated with microvascular complications: approx 5% of diabetics develop severe diabetic retinopathy which can cause blindness, while approx 2% develop diabetic nephropathy and progress to end stage renal disease. Meanwhile, DN is a particularly debilitating complication for patients with long term diabetes and accounts for significant morbidity by predisposing the foot to ulceration and lower extremity amputation. A progressive loss of peripheral nerve function is the underlying cause. The management of DN patients is also the largest contributor to diabetes related health care cost ($5 billion to $10 billion in US alone). There is no current treatment that prevents disease progression in DN patients. The pathogenesis of DN is poorly understood. Chronic low level vascular inflammation has emerged as possible underlying mechanism. Immunohistochemical studies in patient biopsies suggest a possible role for complement, an innate inflammatory pathway activated by tissue injury. Based on clinical studies suggesting a disease modifying role for the lectin pathway of complement in diabetic renal complications, we hypothesized that this pathway may also play a role in DN. To test this hypothesis, we want to determine if blockade of the lectin pathway of complement prevents or treats DN. The hypothesis will be tested in collaboration with Dr. Eva Feldman and the University of Michigan Neuropathy Core Lab, an AMDCC-accredited facility. Monoclonal antibodies against MASP-2, a protease unique to and required for the function of the lectin pathway, will be used for this purpose. We will use obese diabetic db/db mice, a validated preclinical model of DN, to determine if anti-MASP-2 antibody treatment prevents or reverses the hallmark pathogenic features of DN, including the sensory function loss, electrophysiological measures of nerve impairment, and anatomical evidence of nerve fiber loss. Successful demonstration of efficacy in this validate model of DN will provide compelling rationale to pursue anti-MASP-2 antibodies for treatment of DN. Omeros has an anti-human MASP-2 therapeutic antibody currently in preclinical development that that may be useful for patients suffering from this serious, currently untreatable condition. PUBLIC HEALTH RELEVANCE: Tis rojectseekstoexlore heuseo-fMaSniP-2 atioytherayto revet ortrea eroahiccomlicaiosofdiaees.