The p300/CBP inhibitor A485 normalizes psoriatic fibroblast gene expression in vitro and reduces psoriasis-like skin inflammation in vivo

Psoriasis is a chronic inflammatory skin disease that often recurs at the same locations, indicating potential epigenetic changes of lesional skin cells. In this study, we discovered that fibroblasts isolated from psoriatic skin lesions retain an abnormal phenotype even after several passages in culture. Transcriptomic profiling revealed upregulation of several genes, including the EDA splice variant of fibronectin (EDA FN) and Integrin alpha 4 (ITGA4) in psoriatic fibroblasts. A phenotypic library screening of small-molecule epigenetic modifier drugs revealed that selective CBP/p300 inhibitors were able to rescue the psoriatic fibroblast phenotype, reducing the expression levels of EDA FN and ITGA4. In the imiquimod-induced mouse model of psoriasis-like skin inflammation, systemic treatment with A485, a potent CBP/p300 blocker, significantly reduced skin inflammation, immune cell recruitment and inflammatory cytokine production. Our findings indicate that epigenetic re-programming might represent a new approach for the treatment and/or prevention of relapses of psoriasis.