title: A new small molecule for treating inflammation and chorioretinal neovascularization in relapsing-remitting and chronic experimental autoimmune uveitis.
abstract: OBJECTIVE
  We investigated the effect of PP-001, a new small molecule inhibitor of dihydro-orotate 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-γ, 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.
authors.affiliation: Klinikum der Universität München, AG Immunbiologie, Augenklinik, München, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Diedrichs-Möhring
authors.affiliation: 4SC Discovery GmbH, Planegg-Martinsried, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Leban
authors.affiliation: 4SC Discovery GmbH, Planegg-Martinsried, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Strobl
authors.affiliation: Panoptes Pharma GmbH, Wien, Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Obermayr
authors.affiliation: Klinikum der Universität München, AG Immunbiologie, Augenklinik, München, Germany.
authors.forename: Gerhild
authors.initials: G
authors.lastname: Wildner
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D002908:Chronic Disease; D000090722:Dihydroorotate Dehydrogenase; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D051381:Rats; D011917:Rats, Inbred Lew; D012008:Recurrence; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D014605:Uveitis / Q000150:complications* / Q000188:drug therapy / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D000090722:Dihydroorotate Dehydrogenase; D044925:Oxidoreductases Acting on CH-CH Group Donors
keywords: DHODH inhibitor; chronic EAU; rat model; relapsing-remitting EAU; small molecule