Type 1 diabetes is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic ( cells. Several pro-inflammatory cytokines, such as interleukin 1 beta, IL-1beta, Tumor necrosis factor alpha (TNFalpha) and Interferon gamma (IFN-gamma) participate in the immune destruction of beta cells in the islet. Furthermore, interleukin 12 (IL-12) by inducing Th1 cell development has been shown to be an important factor in Type 1 diabetes development. Recurrence of autoimmune damage to transplanted islets also is one factor limiting the full realization of reversal of Type 1 diabetes with transplantation. Therefore, development of new methods to prevent autoimmune damage to beta cells or its recurrence after transplantation could provide a major advance in the field. Lisofylline (LSF) is an anti-inflammatory compound that has been shown to block IL-12 signaling and Th1 cell development. LSF can reduce IL-1-induced beta dysfunction in isolated rat beta cells. New results indicate that LSF can prevent cytokine-induced damage in part by maintaining normal mitochondrial function in beta cells. In addition, data suggests that LSF can significantly reduce spontaneous Type 1 diabetes development in the NOD mouse. However, LSF will have limited use clinically since it has a very short half-life and almost no oral bioavailability and is a relatively weak agent, requiring 20muM concentration in vitro for these effects to be seen. The current pilot proposal will use a focused combinatorial chemistry design to develop more potent, selective, and orally bioavailable anti-inflammatory agents with the same spectrum of activity of LSF.
Aim #1 will be to design and synthesize this library and evaluate agents likely to be orally stable.
Aim #2 will be to screen candidates with potential oral stability and absorption using both the beta cell protection assays and IL-12 signaling assays we have developed.
Aim #3 will test the 2 lead compounds in the NOD mouse to determine their effects in preventing Type 1 diabetes development. Functional and histological studies will be performed. The ultimate goal of this proposal is to identify a lead oral candidate for further detailed in vitro and in vivo development for a Phase 1/2 clinical trial to prevent Type 1 diabetes. This same compound(s) should also provide benefit to maintain beta cell function after islet cell transplantation.
| Cui, Peng; Macdonald, Timothy L; Chen, Meng et al. (2006) Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes. Bioorg Med Chem Lett 16:3401-5 |
| Yang, Zandong; Chen, Meng; Ellett, Justin D et al. (2004) The novel anti-inflammatory agent lisofylline prevents autoimmune diabetic recurrence after islet transplantation. Transplantation 77:55-60 |
| Yang, Zandong; Chen, Meng; Ellett, Justin D et al. (2004) Autoimmune diabetes is blocked in Stat4-deficient mice. J Autoimmun 22:191-200 |
