MASP-2 Antibodies for Diabetic Neuropathy

描述(申请人提供)：MASP-2计划的总体目标是开发一种阻断MASP-2功能的单抗，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目标是验证抗MASP-2治疗糖尿病神经病变(DN)的有效性。在发达国家，糖尿病的发病率和患病率不断上升。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，尽管即使是最好的做法也不能完全预防高血糖。长期糖尿病经常与微血管并发症有关：大约5%的糖尿病患者发展为严重的糖尿病视网膜病变，可导致失明，而大约2%的患者发展为糖尿病肾病并进展为终末期肾脏疾病。同时，对于长期糖尿病患者来说，糖尿病肾病是一种特别令人虚弱的并发症，由于容易导致足部溃疡和下肢截肢，因此导致了显著的发病率。周围神经功能的进行性丧失是根本原因。糖尿病肾病患者的管理也是糖尿病相关医疗费用的最大贡献者(仅在美国就有50亿至100亿美元)。目前尚无预防糖尿病肾病患者病情进展的治疗方法。糖尿病肾病的发病机制尚不清楚。慢性低水平的血管炎症已成为可能的潜在机制。免疫组织化学研究表明，补体可能与补体有关，补体是一种由组织损伤激活的先天炎症途径。根据临床研究提示补体的凝集素途径在糖尿病肾脏并发症中具有改善疾病的作用，我们推测这一途径在糖尿病肾病中也可能起作用。为了验证这一假设，我们想要确定阻断补体的凝集素途径是否可以预防或治疗糖尿病肾病。这一假设将与伊娃·费尔德曼博士和密歇根大学神经病变核心实验室合作进行验证，密歇根大学神经病变核心实验室是AMDCC认证的机构。抗MASP-2的单抗将用于这一目的，MASP-2是凝集素途径所特有的一种蛋白酶，也是凝集素途径功能所必需的。我们将使用肥胖的糖尿病db/db小鼠，一个经过验证的糖尿病肾病临床前模型，以确定抗MASP-2抗体治疗是否可以预防或逆转糖尿病肾病的标志性致病特征，包括感觉功能丧失、神经损伤的电生理指标以及神经纤维丢失的解剖学证据。这一糖尿病肾病验证模型的有效性的成功证明将为寻求抗MASP-2抗体治疗糖尿病肾病提供令人信服的理论基础。Omeros有一种抗人MASP-2治疗性抗体，目前正在进行临床前开发，这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：这项研究的目的是为了预防或治疗癌症。

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.