A New Small Molecule For Treating Inflammation and Chorioretinal Neovascularization in Relapsing-Remitting and Chronic Experimental Autoimmune Uveitis

作者：Diedrichs Moehring Maria; Leban Johann; Strobl Stefan; Obermayr Franz; Wildner Gerhild^*

来源：Investigative Ophthalmology & Visual Science, 2015, 56(2): 1147-1157.

DOI：10.1167/iovs.14-15518

• chronic EAU
• DHODH inhibitor
• relapsing-remitting EAU
• rat model
• small molecule

PURPOSE. We investigated the effect of PP-001, a new small molecule inhibitor of dihydroorotate dehydrogenase in two experimental rat experimental autoimmune uveitis (EAU) models: a spontaneously relapsing-remitting model and a monophasic/chronic disease model that results in late chorioretinal neovascularization. Both of the diseases are induced by immunization with autoantigen peptides.
METHODS. Prevention was tested using daily oral applications of PP-001 after immunization with the retinal S-antigen peptide PDSAg (for induction of monophasic uveitis and neovascularization) or the interphotoreceptor retinoid-binding protein peptide R14 (for induction of spontaneously relapsing-remitting EAU). Treatment to inhibit relapses and neovascularization was tested using PP-001 daily after the first attack of R14-induced or after onset of PDSAg-induced EAU. Uveitis was graded clinically and histologically. The effect of PP-001 on cytokine secretion and proliferation was evaluated using rat T-cell lines.
RESULTS. Preventive feeding of PP-001 abrogated both types of EAU. Starting treatment after the resolution of the first attack led to a significant reduction of the number and intensity of relapses in R14-induced EAU. PP-001-treatment initiated after onset or after peak of PDSAg-induced EAU significantly reduced neovascularization (as determined by histology). Proliferation of antigen-specific T-cell lines and secretion of IFN-gamma, IL-17, IL-10, IP-10, and VEGF were efficiently suppressed by PP-001.
CONCLUSIONS. We investigated a new dihydroorotate dehydrogenase inhibitor as treatment for primary and recurrent disease in relapsing-remitting and chronic rat models of experimental autoimmune uveitis. The small molecule compound PP-001 suppressed proliferation and cytokine secretion of autoreactive T cells (i.e., IFN-g, IL-17, and VEGF) and chorioretinal neovascularization in chronic EAU.

• 出版日期2015-2