Possible psoriasis drug target identified

Studying environmental triggers

Winge and Marinkovich tried to find other options for patients by eavesdropping on the skin’s role in the disease process. That meant considering environmental triggers, which led them to a small molecule, called Rac1, known to play a role in both wound repair and in strep infection.

“Both of these processes activate a small protein called Rac1,” said Marinkovich. “So we wondered if Rac1 was somehow involved in triggering psoriasis in susceptible people.”

When activated, Rac1 is believed to promote the proliferation of cells in the epidermis, as well as send signals to activate the immune system. Under normal conditions, this is a necessary response to heal after an injury. But over-proliferation and over-inflammation could have detrimental effects. Interestingly, some genetic mutations that have been linked to psoriasis affect molecules that are involved in many of the same signaling pathways as Rac1.

The researchers consistently found that Rac1 was highly activated in biopsies of psoriatic skin from 20 people with the condition. When they artificially activated Rac1 in the skin of laboratory mice, the animals exhibited similar symptoms as human patients.

“They had scaling of the skin and arthritis in their joints that precisely mimics what we’ve seen in the clinic,” Marinkovich said. The effect was abolished, however, in mice engineered to lack immune cells called T cells —  further confirming the immune system’s role in the disorder.

Blocking protein’s activity

Finally, blocking the activity of Rac1 in patches of psoriatic human skin that had been transplanted onto the backs of mice reversed the skin hyperplasia and reduced the recruitment of immune molecules known as cytokines to the transplanted patch.

“Psoriasis is one of the most prevalent skin diseases in the world,” said Marinkovich. “But it’s been difficult to study due to the complex interplay between genetic and environmental influences. Now we’ve learned that targeting Rac1 activation in the skin, rather than the immune system’s role in the disease, may be a way to treat the disease without needing to suppress the immune system.”

"The study is the first to find a molecule linking genetic susceptibility to the disease with the environmental causes known to trigger it."

Marinkovich and his colleagues plan to continue their study of what causes Rac1 activation in the epidermis.

“The study is the first to find a molecule linking genetic susceptibility to the disease with the environmental causes known to trigger it,” Marinkovich said. “We’d like to understand all the steps between these gene defects and Rac1 activation. Then we can try to identify drugs that can down-regulate the cause of abnormal Rac1 activation in psoriasis. The availability of a cream or other topical application could completely change the way we treat psoriasis in the clinic.”

Other Stanford co-authors of the study are former visiting scientists Bungo Ohyama, MD, PhD, Wei Li, MD, and Teruhiko Makino MD, PhD; former research assistant Clara Dey; former graduate student Lisa Boxer, PhD; postdoctoral scholar Nazanin Ehsani-Chimeh, MD; former medical students Allison Truong, MD, and Diane Wu, MD; former postdoctoral scholars Daniela Starcevic, PhD, and Elizabeth Waterman, PhD; research assistant Ngon Nguyen; and professor of dermatology Paul Khavari MD, PhD.

The study was supported by the U.S. Department of Veterans Affairs, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant AR47223), the National Psoriasis Foundation, the European Union’s Seventh Framework Program, the Swedish Society of Medicine and the Fernstrom Foundation.

Stanford’s Department of Dermatology also supported the work.

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Possible psoriasis drug target identified