AI-guided CRISPR screening reveals therapeutic targets in psoriasis

Area of Science:

• Dermatology
• Genomics
• Pharmacology

Background:

• Psoriasis impacts over 125 million globally, with current biologics targeting the IL-17/IL-17RA axis being effective but limited by systemic administration and cost.
• Developing topical small-molecule drugs requires understanding IL-17 receptor A (IL17RA) regulation in keratinocytes, key cells in psoriatic lesions.

Purpose of the Study:

• To identify novel regulators of surface IL-17 receptor A (IL17RA) in human epidermal keratinocytes.
• To validate these regulators as potential therapeutic targets for topical psoriasis treatments.

Main Methods:

• Conducted a genome-wide CRISPR knockout screen in primary human epidermal keratinocytes to identify IL17RA regulators.
• Utilized experimental enrichment and VirtualCRISPR, an AI framework, to prioritize screening hits.
• Validated 5-lipoxygenase (ALOX5) and oxytocin receptor (OXTR) as regulators of IL17RA.

Main Results:

• Identified ALOX5 and OXTR as novel regulators of IL17RA with distinct cell-intrinsic mechanisms.
• Demonstrated that topical zileuton (ALOX5 inhibitor) and cligosiban (OXTR antagonist) suppressed psoriasiform dermatitis in mice.
• Showed efficacy comparable to systemic anti-IL17RA antibodies in a mouse model.

Conclusions:

• The study presents an efficient AI-guided approach for therapeutic discovery, linking genetic screening to biological validation.
• ALOX5 and OXTR represent promising targets for developing novel topical small-molecule therapies for psoriasis.
• This research offers a pathway to alternative treatments for patients unsuitable for current biologic therapies.