Rac Inhibitor Drugs

A new study shows that blocking a signaling molecule known as Rac may prevent new lesions from forming in the guts of patients with Crohn’s disease.

Kaushal Parikh, a researcher at University Medical Center Groningen (IMCG) in the Netherlands, found that using Rac inhibitor drugs already on the market may put the disease—a type of inflammatory bowel disease (IBD)—into remission. His work was published today in Science.

The researchers studied non-inflamed and inflamed human gut tissue and found that the bodies of people without inflamed gut tissue naturally suppressed Rac signaling. Suppressing Rac helps the body defend itself against bacterial infections, which may explain why Rac inhibition reduces ulcers and inflammation. Researchers say that Rac inhibitor drugs could force the disease into remission.

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Treatment May Be Lifelong

Dr. Maikel P. Peppelenbosch, a researcher at Erasmus University Medical Center Rotterdam in the Netherlands, said the research indicates that moderate inhibition of Rac, or another signaling molecule known as Pak, might be useful for preventing flare ups or getting patients into remission.

“Ideally, we envision that we would bring patients into remission with conventional therapy like steroids or maybe anti-TNF, and subsequently give a low dose of a Rac inhibitor to maintain remission,” Peppelenbosch said. Anti-TNF drugs, including Enbrel and Humira, are commonly used to treat inflammatory autoimmune diseases like rheumatoid arthritis (RA).

The scientists are looking to start a human clinical trial based on their research. Peppelenbosch said, however, that a treatment using Rac inhibitors would likely have to be lifelong in order to keep Crohn's disease at bay.

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Side Effects, Exact Dosing Could Be Hurdles

Kim E. Barrett, Ph.D., a professor at the University of California, San Diego School of Medicine, said that the study adds “another piece to the puzzle” of how changes in cell signaling, particularly related to immunity, may lead to inflammatory bowel diseases. She said that Rac inhibitors are already being studied to treat autoimmune diseases like RA. 

“While this [study] indicates promise, the fact that Rac1 is involved in many cellular processes implies that it may be difficult to target this model to improve IBD outcomes without the risk of side effects,” she said.

“These are therefore ‘Goldilocks’ drugs… too much or too little and there is no, or even the opposite of, the desired effect to increase innate immunity,” she added. “It means that you would have to get the dose just right, which is not necessarily easy to achieve in clinical practice.”

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