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The p300/CBP Inhibitor A485 Normalizes Psoriatic Fibroblast Gene Expression In Vitro and Reduces Psoriasis-Like Skin
Jihye Kim1, Yuliang He1, Sabrina Tormen1
1Institute of Pharmaceutical Sciences (IPW), Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland.
The Journal of Investigative Dermatology
|September 29, 2022
Summary
Psoriasis fibroblasts show abnormal gene expression due to potential epigenetic changes. CBP/p300 inhibitors reversed these changes and reduced inflammation in a mouse model, suggesting epigenetic reprogramming as a psoriasis treatment.
Area of Science:
- Dermatology
- Epigenetics
- Molecular Biology
Background:
- Psoriasis is a chronic inflammatory skin condition characterized by recurring lesions.
- Recurrence suggests underlying epigenetic alterations in skin cells.
- Psoriatic fibroblasts exhibit persistent abnormal phenotypes in vitro.
Purpose of the Study:
- To investigate epigenetic dysregulation in psoriatic fibroblasts.
- To identify potential therapeutic targets for psoriasis treatment.
Main Methods:
- Fibroblast isolation and culture from psoriatic lesions.
- Transcriptomic profiling to identify gene expression changes.
- Phenotypic screening of small-molecule epigenetic modifiers.
- In vivo validation using an imiquimod-induced mouse model.
Main Results:
- Psoriatic fibroblasts overexpressed genes like fibronectin extra domain A and ITGA4.
- Selective CBP/p300 inhibitors normalized fibroblast phenotype and gene expression.
- Systemic administration of CBP/p300 inhibitor A485 reduced skin inflammation, immune cell infiltration, and cytokine production in mice.
Conclusions:
- Epigenetic reprogramming by targeting CBP/p300 is a promising therapeutic strategy for psoriasis.
- This approach may offer a new way to treat psoriasis and prevent lesion recurrence.
