title: Development of a Topical Treatment for Psoriasis Targeting RORγ: From Bench to Skin.
abstract: BACKGROUND
  Psoriasis is a chronic inflammatory skin disorder involving marked immunological changes. IL-17-targeting biologics have been successful in reducing the disease burden of psoriasis patients with moderate-to-severe disease. Unfortunately, the stratum corneum prevents penetration of large molecule weight proteins, including monoclonal antibodies. Thus, for the majority of psoriasis patients ineligible for systemic treatments, a small molecule targeting RORγt, the master regulator of IL-17 family cytokines, may represent an alternative topical medicine with biologic-like efficacy.
  
  
  RESULTS
  The preclinical studies described in this manuscript bridge the gap from bench to bedside to provide the scientific foundation for a compound entering clinical trials for patients with mild to moderate psoriasis. In addition to several ex vivo reporter assays, primary T cell cultures, and the imiquimod mouse model, we demonstrate efficacy in a newly developed human ex vivo skin assay, where Th17-skewed cytokine expression is induced from skin-resident immune cells. Importantly, the skin barrier remains intact allowing for the demonstration of topical drug delivery. With the development of this novel assay, we demonstrate potent compound activity in the target tissue: human skin. Finally, target engagement by this small molecule was confirmed in ex vivo lesional psoriatic skin.
  
  
  CONCLUSIONS
  Our work describes a progressive series of assays to demonstrate the potential clinical value of a novel RORγ inverse agonist small molecule with high potency and selectivity, which will enter clinical trials in late 2015 for psoriasis patients.
authors: Discovery and Preclinical Development, Stiefel, a GSK company, Research Triangle Park, North Carolina, United States of America.
authors: Susan H
authors: SH
authors: Smith
authors: Discovery and Preclinical Development, Stiefel, a GSK company, Research Triangle Park, North Carolina, United States of America.
authors: Carlos E
authors: CE
authors: Peredo
authors: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America.
authors: Yukimasa
authors: Y
authors: Takeda
authors: Discovery and Preclinical Development, Stiefel, a GSK company, Research Triangle Park, North Carolina, United States of America.
authors: Thi
authors: T
authors: Bui
authors: Discovery and Preclinical Development, Stiefel, a GSK company, Research Triangle Park, North Carolina, United States of America.
authors: Jessica
authors: J
authors: Neil
authors: MDR/PTS, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors: David
authors: D
authors: Rickard
authors: Discovery and Preclinical Development, Stiefel, a GSK company, Research Triangle Park, North Carolina, United States of America.
authors: Elizabeth
authors: E
authors: Millerman
authors: Discovery and Preclinical Development, Stiefel, a GSK company, Research Triangle Park, North Carolina, United States of America.
authors: Jean-Philippe
authors: JP
authors: Therrien
authors: Flexible Discovery Unit, GlaxoSmithKline, Les Ulis Cedex, France.
authors: Edwige
authors: E
authors: Nicodeme
authors: Flexible Discovery Unit, GlaxoSmithKline, Les Ulis Cedex, France.
authors: Jean-Marie
authors: JM
authors: Brusq
authors: Respiratory Therapeutic Area, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, United Kingdom.
authors: Veronique
authors: V
authors: Birault
authors: Flexible Discovery Unit, GlaxoSmithKline, Les Ulis Cedex, France.
authors: Fabrice
authors: F
authors: Viviani
authors: Discovery and Preclinical Development, Stiefel, a GSK company, Research Triangle Park, North Carolina, United States of America.
authors: Hans
authors: H
authors: Hofland
authors: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America.
authors: Anton M
authors: AM
authors: Jetten
authors: Discovery and Preclinical Development, Stiefel, a GSK company, Research Triangle Park, North Carolina, United States of America.
authors: Javier
authors: J
authors: Cote-Sierra
mesh_terms: D000279:Administration, Cutaneous; D000634:Aminoquinolines; D000818:Animals; D004353:Drug Evaluation, Preclinical; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D000077271:Imiquimod; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000494:pharmacology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D010539:Permeability; D061251:Primary Cell Culture; D011565:Psoriasis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000494:pharmacology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D057170:Translational Research, Biomedical
chemical_list: D000634:Aminoquinolines; D007155:Immunologic Factors; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D054852:Small Molecule Libraries; D008156:Luciferases; D000077271:Imiquimod