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.