A new small molecule for treating inflammation and chorioretinal neovascularization in relapsing-remitting and chronic experimental autoimmune uveitis

Invest Ophthalmol Vis Sci. 2014 Dec 16;56(2):1147-57. doi: 10.1167/iovs.14-15518.

Abstract

Purpose: 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.

Keywords: DHODH inhibitor; chronic EAU; rat model; relapsing-remitting EAU; small molecule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use*
  • Autoimmune Diseases / complications*
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / pathology
  • Choroidal Neovascularization / drug therapy*
  • Choroidal Neovascularization / etiology
  • Choroidal Neovascularization / pathology
  • Chronic Disease
  • Dihydroorotate Dehydrogenase
  • Disease Models, Animal
  • Female
  • Male
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Rats
  • Rats, Inbred Lew
  • Recurrence
  • Retinal Neovascularization / drug therapy*
  • Retinal Neovascularization / etiology
  • Retinal Neovascularization / pathology
  • Uveitis / complications*
  • Uveitis / drug therapy
  • Uveitis / pathology

Substances

  • Anti-Inflammatory Agents
  • Dihydroorotate Dehydrogenase
  • Oxidoreductases Acting on CH-CH Group Donors