Aryl Hydrocarbon Receptor Innate Immune Modulators for Treatment of Inflammatory Bowel Disease
Abstract
This Technology/Therapeutic Development Award application is in the FY20 topic area of Inflammatory Bowel Disease (IBD). IBD, which refers to either Crohn’s disease or ulcerative colitis, affects over 3 million adults in the United States with 70,000 new cases diagnosed each year. The majority of individuals are diagnosed in their late teens, 20s, and 30s, often among those with a family history of IBD, suggesting that inherited genetic factors may increase risk. IBD is characterized by chronic inflammation of the gastrointestinal (GI) tract or “gut” with diarrhea, abdominal pain, bloody stools, and weight loss, inevitably resulting in severe damage to the GI tract and an increased risk of colon cancer. The cause of IBD is not well understood, but appears to be the result of a faulty immune system, which responds incorrectly to gut bacteria and bacterial byproducts or other ingested substances as a consequence of excessive permeability or leakiness of the intestinal barrier. This inappropriate immune response, which leads to excessive inflammation, induces further disruption and dysfunction of the intestinal barrier with changes in the microorganisms normally found in the gut and increased vulnerability to bacterial invasion of the gut wall. Thus, loss of integrity of the intestinal barrier, which is lined by epithelial cells, is both a cause and consequence of IBD. The inability to maintain a healthy intestinal barrier has also been recognized as a factor leading to celiac disease, irritable bowel syndrome, obesity-associated diabetes and may increase susceptibility and worsen the severity of a variety of intestinal infections. Currently available drugs that suppress the immune system or block inflammation have shown some benefit, but over time lose their potency and significantly increase the risk of infection and cancer. At least one-third of all patients with IBD do not respond to existing therapies, and there is no marketed drug that is directly targeted at restoring or maintaining intestinal barrier function. The gut immune system is normally responsible for maintaining and restoring the integrity of the intestinal barrier while promoting the growth of normal gut microorganisms and providing protection from those that cause disease. An important regulator of the gut immune system is the aryl hydrocarbon receptor (AHR), which is a protein found in gut epithelial and immune cells that responds to small molecules produced either as byproducts of our diet or from the microorganisms in our gut. An inadequate diet, an imbalance in healthy gut microorganisms, or other genetic factors may lead to a deficiency of those small molecules needed to activate AHR, which is believed to increase the risk of IBD, as well as the severity and duration of symptoms. Insufficient activation of AHR may also contribute to the risk and severity of a variety of other diseases that have been attributed to the loss of a healthy gut barrier. First-generation drugs that regulate AHR activity have shown some promise in animal models and in small studies of patients, but have been limited by very low activity and toxic side effects, which have prevented them from being approved for use in patients. Using cutting-edge techniques in biology, chemistry, and computer science, we have recently discovered a new class of highly potent small molecules that regulate AHR activity, can be administered orally, appear to be very safe, and stimulate the gut immune system to rapidly accelerate healing of the intestinal barrier in an animal model of IBD with restoration of a healthy epithelial lining. Importantly, we have also observed that human immune cells obtained from healthy adult volunteers and from patients with active IBD respond to our drugs with secretion of biologically active molecules that both maintain and restore a healthy gut barrier. The objective of the studies in this application is to identify one or more promising drug candidates that are su
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110369
Entities
People
- Elliot Chaikof
Organizations
- Beth Israel Deaconess Medical Center
- United States Army