Researchers have developed an innovative approach to integrating genomic data with research on animal models, and used it to identify a potential new target for treating psoriasis. Psoriasis is an inflammatory skin condition which affects more than a million people in the U.S.

Ten percent of patients with psoriasis use biologics – mainly TNF-blockers such as Enbrel (etanercept, Amgen Inc.), Humira (adalimumab, Abbvie Inc.), Remicade (infliximab, Johnson & Johnson) and Simponi (golimumab, Janssen Biotech Inc.). Experimental drugs also target cytokines such as IL-17 and IL-23.

The target, the kinase PIM1, is induced by the inflammatory cytokine interleukin-22 (IL-22). While previous research had implicated IL-22 in inflammatory skin diseases, PIM-1 “had never been associated before with psoriasis,” Frank Nestle told BioWorld Today.

Nestle is at King’s College London and the senior author of the paper describing the findings, which appeared in the Feb. 12, 2014, issue of Science Translational Medicine.

Nestle and his team were able to identify PIM-1 as a target by integrating many different types of data. Genomics, with the vast amounts of data it generates as both sequencing and computing become ever cheaper, has given researchers a new type of challenge.

“We have all this genomic data,” Nestle said. “We have to tackle this complexity and integrate it into testable hypotheses. What we tried to do in this paper is to move back and forth” between genomic data and those animal models.

In the work now published in Science Translational Medicine, gene expression data in patients provided “a psoriasis galaxy” in the form of a comprehensive view of the differences in gene expression between normal and psoriatic skin.

A xenotransplantation model of psoriasis that grafts human skin onto immunosuppressed mice that Nestle and his colleagues had developed earlier, in turn, allowed them to zero in on the molecular details of that galaxy.

In their studies, Nestle and his colleagues investigated the role of the IL-22 because previous work had hinted it might play a role in inflammatory skin conditions and its expression was increased in psoriatic skin samples. They looked at the effects of injecting IL-22 on normal skin in their mouse model, and found that those skin patches became psoriasis-like, with the epidermal layer of the skin thickening in much the same way it does in psoriasis.

Conversely, treating psoriasis animals with an anti-IL-22 antibody reduced inflammation. The effects of blocking IL-22 were comparable to those of blocking TNF, the gold standard in psoriasis and target of choice in current psoriasis biologics.

The team then compared the gene expression changes that occurred in IL-22 treated normal skin with gene expression data from psoriatic skin, psoriatic skin that was treated with an IL-22 antibody, and skin cells treated with IL-22 in cell culture, and identify “hub genes” that were critical for IL-22’s effects in psoriasis.

That analysis pointed to the kinase PIM-1 as such a hub gene, and so the team went on to test the role of this kinase directly. They found that knockout mice lacking the kinase were partially protected from developing psoriasis in response to the immune activator imiquimod, which could induce psoriasis when applied to the skin of normal animals. They also treated psoriatic animals with a small-molecule PIM-1 inhibitor, and found that it could block the effects of imiquimod.

PIM-1 kinase, which phosphorylates the amino acids serine and threonine, is best known to the biopharma community as an oncogenic kinase, and blockers are in early stage development. Astra-Zeneca plc’s AZD-1208 and CXR Biosciences Ltd.’s CXR-1002 are in phase I, and a number of companies have preclinical programs.

IL-22 antagonists have been tested in dermatological disease, but several such programs have been discontinued.

In their paper, Nestle and his team expressed their hope that “our data might contribute to a clinical reevaluation of efforts blocking the IL-22 pathway in inflammatory skin disease.”