Development of Novel Vitamin D3 Analogs, 19-Norvitamin D3 with Higher Potency for Topical Treatment of Psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by morphological features of erythema, induration and scaling. The active form of vitamin D3, 1,25(OH)2D3 or calcitriol, is known to exert multiple beneficial biological activities to treat psoriasis, however, high dose of 1,25(OH)2D3 can cause hypercalcemia. Thus, analogs of 1,25(OH)2D3 that are less calcemic but exhibit potent activity are the goal for us to develop a better therapeutic agent. Our previous studies demonstrated that MART-10, one of the four 19-norvitamin D3 analogs exhibits higher potency (＞10 fold) to cause cell cycle arrest and inhibit cell growth. We also demonstrated for the first time that MART-10 can also inhibit the angiogenesis both in vivo and in vitro. Together with the biological actions of 1, 25(OH)2D3 such as enhancing skin barrier function and the immunomodulatory activity, we propose the hypothesis that four 19-norvitamin D3 analogs including MART-10, MART-11, 14-epi-MART-10 and 14-epi-MART-11 could exert excellent anti-psoriatic efficacy for the topical treatment using IMQ-induced psoriasis animal model. More importantly, these 1, 25(OH)2D3 analogs are proved to be much more potent and much less chance to cause systemic hypercalcemia which is worth to be further investigated. Besides in vivo animal study, we will also investigate the effects of four analogs using cell cultures including epidermal keratinocytes , vascular endothelial cells and T lymphocytes. Results from this proposal will help us to understand more about the pathogenesis of psoriasis, the molecular mechanism underlying the potential anti-psoriasis effects of four analogs appreciably contribute to the development of a novel treatment for the psoriasis therapy.

Project ID:PC10708-0862
External Project ID:MOST107-2314-B182-036