A novel class of T helper cell, distinct from TH1 and TH2 cells, has been implicated in the development of murine experimentally-acquired encephalomyelitis (EAE), a model of multiple sclerosis (MS). This effector T cell, termed a TH-17 cell, is characterized by release of the highly pro-inflammatory cytokine interleukin 17 (IL- 17). Deficiency of the TH-17 survival factor IL-23, or of IL-17 itself, blocks or substantially inhibits development of EAE and several other autoimmune diseases in mice. The nuclear transcription factor ROR?, an orphan member of the steroid-thyroid-retinoid family of nuclear hormone receptors, is required for differentiation of TH-17 cells. We recently identified ROR? antagonists and showed that these specifically inhibit cytokine- mediated TH-17 but not TH1 formation from na?ve mouse CD4+ T cells in culture. The major objectives of this proposal are to design an ROR? lead antagonist suitable for in vivo studies and to test the hypothesis that such a compound can inhibit the induction of EAE in a rodent model of MS.
In Aim 1, more potent ROR? antagonists will be synthesized based on compounds already identified by the applicant. A selective and bioavailable compound will be chosen for further work.
In Aim 2, the lead ROR? antagonist will be tested in EAE and its effect on TH-17 development investigated.
In Aim 3, we determine whether ROR? antagonists inhibit IL-17 expression in human peripheral blood T cells, confirming a common pharmacology of ROR? ligands in mouse and human. If these feasibility studies successfully demonstrate inhibition of symptoms in rodent EAE by an ROR? antagonist and regulation of IL-17 expression in isolated human T cells, we plan in Phase II to initiate discovery, development and testing of a pre-clinical drug candidate. The long-term goal of this work is to create an entirely new class of orally-bioavailable, anti-inflammatory drug for MS and other forms of autoimmune disease. ?
TO PUBLIC HEALTH Multiple sclerosis (MS) is a painful and crippling disease that affects an estimated 350,000 individuals in the U.S. alone. The incidence among women is twice that of men. The annual cost in terms of direct care and lost productivity has been estimated at $7 billion/year. Therapeutic treatments for MS are limited and most have serious side effects. Recent basic medical research has described a novel actor in the immune system: a specialized immune cell that has a central causative role in animal models of MS. By developing drugs that selectively target this new category of immune cell, we have the opportunity to develop safer therapies for MS. ? ? ?