Inflammatory bowel disease (IBD) encompasses a spectrum of autoimmune disorders effecting up to 2,000,000 Americans. Although anti-TNF-alpha therapies are effective in IBD, their use is associated with systemic side effects including re-activation of latent pathogens, cancer, and the formation of autoantibodies. Some patients are inherently resistant to anti-TNF-alpha drugs, and over time, almost half of all patients that initially respond, develop resistance. Side effects and gaps in efficacy of current treatments result in significant morbidity for IBD patients and a need for better treatment options. Recent studies have demonstrated that gut-resident pathogenic immune cells driving IBD have a metabolic phenotype wherein they abnormally rely on oxidative phosphorylation for survival and effector function. Niclosamide is a gut-restricted salicylanilide antihelmintic drug possessing an outstanding safety profile based on human use over 50 years. Its antihelmentic effect results from uncoupling mitochondria of cestodes, disrupting their oxidative phosphorylation and causing death of the parasites. Here we describe an experimental therapeutic approach leveraging the chemical biology of niclosamide to target pathogenic immune cells in IBD, that similar to cestodes depend on oxidative phosphorylation. Results in several preclinical models of IBD. highlight the potential of niclosamide to be developed as a new, cost-effective treatment for IBD (both mild-to-moderate and moderate-to-severe forms of the disease) and underlie the rationale for current clinical evaluation of the drug in ulcerative colitis.

Small molecule approaches to the treatment of IBD

256th National Meeting (2018)

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