Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic p-cells. There is no effective drug therapy to prevent the development of T1D, and the best therapeutic option for T1D is islet transplantation. However, transplantation has severe limitations: (a) limited availability of donor islets, (b) toxicity of immunosuppressant given to prevent rejection of transplanted islets. Thus there is a need for novel drug therapies which can either (1) prevent or delay the development of T1D after early detection, or (2) prevent transplant rejection used alone, or in combination with lower doses (less toxic) of immunosuppressant. We have developed a novel lipoic acid analog, MM040 that may meet these medical needs. MM040 is a cell-permeable free radical scavenger which can prevent oxidative stress in cells. Islet destruction in T1D is caused primarily by oxidative stress in pancreatic p-cells induced by inflammatory mediators (IL-lp, TFNa, IFNy, nitric oxide). Macrophages which infiltrate the islets in T1D are a major source of these mediators, and MM040 inhibits the release of these mediators from macrophages. We hypothesize that MM040 can both prevent oxidative stress in p-cells induced by inflammatory mediators, and prevent the release of these mediators from macrophages. The first Phase I goal is to test the efficacy of MM040 in the prevention of T1D and rejection of transplanted islets in the NOD mouse model. We will determine if MM040 can (1) inhibit the adoptive transfer of T1D after injection of diabetogenic T-cells, and (2) inhibit the rejection of islets transplanted in diabetic mice. A second Phase I goal is to synthesize 15 novel analogs of MM040 to improve its potency and efficacy. These compounds will be tested in RINmSF rat insulinoma cells and RAW 264.7 macrophage cells. Analogs will be tested for (1) inhibition of cell death, NFicB activation, and NO formation in RINmSF cells exposed to cytokines (IL-1p, TFNa, IFNy),), and (2) inhibition of release of TNFa, IL-1p, and NO in RAW 264.7 cells exposed to LPS + INFy. Phase II goals are to (1) test the best analog in vivo, (2) develop an oral formulation of MM040, determine its PK and toxicity properties, and optimize an oral dosing regimen, (3) determine whether oral MM040 can prevent spontaneous T1D in NOD mice, (4) determine whether MM040 can reduce the dose of immunosuppressant necessary to prevent transplant rejection in mice, (5) assess the ability of MM040 to protect human islets during the isolation process, and increase yield of viable donor islets. The commercial goal is to develop an orally active drug which can prevent or delay onset of T1D, and/or improve the transplantation process by reducing the toxicity of immunosuppression and by increasing donor islet yield. ? ?