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C286 an orally available retinoic acid receptor Beta agonist drug regulates multiple pathways to achieve SCI repair

ABSTRACT: C286 an orally available retinoic acid receptor Beta agonist drug regulates multiple pathways to achieve SCI repair

PROVIDER: PRJNA1115223 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29149966_1.fastq.gz	Fastqsanger.gz
	SRR29149966_2.fastq.gz	Fastqsanger.gz
	SRR29149967_1.fastq.gz	Fastqsanger.gz
	SRR29149967_2.fastq.gz	Fastqsanger.gz
	SRR29149968_1.fastq.gz	Fastqsanger.gz

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Project description:Background and Purpose:  The chemokine receptor CCR6 is important in guiding pathogenic T17 cells that are implicated in numerous autoimmune diseases including psoriasis to sites of inflammation via the chemokine CCL20. On this basis, pharmacological interventions that inhibit CCR6+ immune cell migration provide a novel therapeutic approach for such diseases. However, the translatability from pre-clinical models to human diseases of such an intervention has so far not been assessed in detail. Here, we evaluate the translatability of a preclinical model of Aldara induced skin inflammation to psoriasis with a particular focus on immune cell trafficking and assess the efficacy of the novel, orally available CCR6 antagonist IDOR-1117-2520 in this model. Experimental Approach:  Here, we evaluated the in vivo therapeutic effects of IDOR-1117-2520, a novel, highly selective, potent, and orally available CCR6 small molecule inhibitor, in the Aldara mouse model of skin inflammation. To understand in detail CCR6 inhibition on the inflammatory response, flow cytometry, RNA sequencing, and transcriptome-based cell type deconvolution approaches were used to characterize immune cell migration patterns and to compare the results to publicly available human psoriasis transcriptomics data. Key Results:  IDOR-1117-2520 dose dependently reduced infiltration of CCR6 + immune cells into inflamed skin and was equally efficacious as IL-17 and IL-23 inhibition in reducing inflammation in the skin. Pathway analysis highlighted the strong molecular similarities in immune response between human psoriasis and the Aldara mouse model. Genes associated with the IL-17/IL-23 pathway were prominently expressed in both human psoriasis and in the mouse model. CCR6 inhibition modulated multiple pathways associated with inflammation beyond the proximal IL-17/IL-23 pathway. A chemokine-chemokine receptor interaction map implicated the CCL20-CCR6 as the dominant axis in recruiting pathogenic T17 cells in this model system, as well as in human psoriasis. Conclusion and Implications:  These results suggest that IDOR-1117-2520 could provide a promising novel targeted therapeutic approach to treating psoriasis and, potentially, other autoimmune diseases with an involvement of CCR6/CCL20 axis and the IL-17/IL-23 pathway. The data provide rationale for the further development of IDOR-1117-2520, which is currently being evaluated in a clinical phase 1 trial (ISRCTN28892128).

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C286 an orally available retinoic acid receptor Beta agonist drug regulates multiple pathways to achieve SCI repair

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