Psoriasis is a common, inflammatory disease of the skin characterized by hyper-proliferation of keratinocytes. A variety of antipsoriatic therapies are available, however, due to problems with side effects and variability in clinical response, intense clinical and commercial interest remains in the development of new treatments. Thiazolidinediones, a novel class of compounds that activate the nuclear hormone receptor PPAR gamma, have recently been found to reversibly inhibit the proliferation of both normal and psoriatic human keratinocytes in vitro, and ameliorate the histologic abnormalities of psoriatic skin in organ culture and in the scid mouse/human skin transplant model of psoriasis. In the current proposal, we will: 1) perform pilot studies of the antipsoriatic effects of orally administered thiazolidinediones in humans; 2) investigate the cellular mechanisms that mediate the antipsoriatic effects of thiazolidinediones, and 3) investigate the antipsoriatic potential of a recently developed series of novel thiazolidinediones that are expected to be more effective than existing compounds with respect to ameliorating the epidermal inflammation and hyperproliferation that characterizes psoriasis. By investigating clinical efficacy, by addressing therapeutic mechanisms, and by testing novel thiazolidinediones, the current Phase II studies will significantly advance the potential for Phase III commercial development of thiazolidinediones in the treatment of psoriasis.
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