Genome-Wide CRISPR Screen Reveals New Psoriasis Targets

Summary

Biohub researchers performed what they believe is the first genome-wide CRISPR study of primary human adult skin cells, then used an AI model to mine the results for overlooked drug targets for psoriasis. They found an unlikely candidate: the receptor for oxytocin, a hormone involved in childbirth, and sometimes called the “love hormone” for its additional role in social bonding. As reported in Nature Communications, when the team formulated topical gels containing compounds that would inhibit the oxytocin receptor, as well as another promising target, both gels reduced psoriasis inflammation in mice as effectively as an injected drug used by many patients. “A CRISPR screen at this scale, guided by AI, gave us answers the field has never had access to before, as well as a surprisingly effective potential treatment,” said Shana O. Kelley, president of bioengineering and head of Biohub in Chicago, where scientists are decoding the inflammatory processes that drive a wide range of diseases. Kelley co-led the study with Abdalla M. Abdrabou, lead scientist for Biohub’s Functional Immunogenomics group. “We think of this as a blueprint,” added Abdrabou. “The specific targets we found in psoriasis are exciting, but the method itself is what we are most proud of. This is a generalizable way to find treatments that those of us studying disease wouldn’t even know to look for.” Psoriasis affects roughly 125 million people worldwide. For mild cases, topical therapies, such as steroid creams, can often manage symptoms effectively. But for the many patients with moderate-to-severe disease, systemic therapies become necessary — and all come with trade-offs. “Biologics” that target immune signaling proteins must be injected, can cost tens of thousands of dollars per year, and carry risks from broad immune suppression. Recently approved therapies in pill form may reduce the burden of injections, but the drugs still circulate throughout the body, affecting immune pathways beyond the skin. What has been missing is an approach that acts locally in the skin cells where psoriasis begins, targeting disease pathways specific enough to not broadly perturb immune function. Getting there requires understanding the biology of keratinocytes — the outermost skin cells that are the primary site of psoriatic disease — at a level of detail the field has lacked, because these cells have been…