Dataset Information

Development of a Topical Treatment for Psoriasis Targeting ROR?: 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 ROR?t, the master regulator of IL-17 family cytokines, may represent an alternative topical medicine with biologic-like efficacy.

Methods and findings

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 ROR? inverse agonist small molecule with high potency and selectivity, which will enter clinical trials in late 2015 for psoriasis patients.

SUBMITTER: Smith SH

PROVIDER: S-EPMC4752338 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Development of a Topical Treatment for Psoriasis Targeting RORγ: From Bench to Skin.

Smith Susan H SH Peredo Carlos E CE Takeda Yukimasa Y Bui Thi T Neil Jessica J Rickard David D Millerman Elizabeth E Therrien Jean-Philippe JP Nicodeme Edwige E Brusq Jean-Marie JM Birault Veronique V Viviani Fabrice F Hofland Hans H Jetten Anton M AM Cote-Sierra Javier J

PloS one 20160212 2

<h4>Background</h4>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 regulato ...[more]

PMID: 26870941

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