Research Project
9336475
Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and the leading cause of end-stage renal disease in Western and Asian countries. The current medical management of diabetes to prevent its complications include tight glycemic control and strict management of blood pressure, these established treatments delay the onset and the progression of DN; however, they have little effect on reversing the progression of DN. Hence, novel therapies are needed to safely target the other underlying pathophysiological mechanisms and halt or reverse DN. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of Treg by direct binding to its high affinity receptor. It has been shown that treatment with low-dose (1-3% cancer model dose) rIL2 increased anti-inflammatory Treg cells and M2 type macrophage and inhibited pathogenic interferon-? secreting T helper type 1 cells in the abdominal fat that led to improvement of glucose tolerance and insulin sensitivity of mice on high fat diet. Hence, restoration of VAT Treg cells with low-dose IL2 may offer a novel strategy for prevention and treatment of T2D and its associated diabeticnephropathy. However, several drawbacks exist for current low-dose rIL2 therapy, including a short half life, propensity to in vitro aggregation causing adverse local reaction at injection sites, and potentially narrow therapeutic window. We have designed a proprietary IL2-based therapy that will enable selective stimulation of Tregs with an extended half life, minimal in vitro aggregation, and broad therapeutic window. In the proposed Phase I SBIR study, we will evaluate the dose-response of the drug candidate in the db/db murine model of DN. Specific Aim. To determine whether weekly treatment with mAPT602 (s.c.) halts or reverses DN progression in the db/db diabetic model of mice undergoing uninephrectomy without significant side effects. The long-term goal is to develop the drug candidate as a safe and effective therapy to halt or reverse DN.
