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Novel Approach to Treat IBD:  Targeting Claudin-2 with Small Molecule

Christopher Weber, MD PhD

THE PROBLEM

Existing treatments of IBD range from immunosuppressive therapies to surgical interventions, many have limited efficacy, and can be associated with severe complications. Thus, novel approaches are needed. A central pathological feature of IBD is the disfunction of the epithelial tissue, thin tissues comprised of compact cells that cover all the exposed surfaces of the body, underscoring the need for therapeutic strategies targeting the epithelial barrier.

THE HYPOTHESIS

• • Tight junctions are areas where the membranes of two abutting cells form a barrier connected by proteins called claudins.
  • Targeting claudin-2 could be a novel approach to treating IBD.
  • Claudin-2 expression is elevated in IBD and seems to be driven by inflammatory responses signaled by cells called cytokines.
  • Blocking these channels with a new class of Claudin Channel Blockers (CCBs) can reduce diarrhea and colitis in mouse models of IBD and reduce transepithelial water flow in human organoid models.

THE RESEARCH PLAN

• Adopt a machine learning-assisted approach for the rational design of improved CCBs.
• Examine the efficacy of the newly designed CCBs in model intestinal epithelium and organoids derived from patients with inflammatory bowel disease.

THE GOALS

• Create an algorithm that will predict the efficacy for a molecule to target claudin-2 dependent barrier function.
• Develop approximately ten novel claudin-2 channel blockers for animal testing.
• Develop a non-immunosuppressive strategy targeting intestinal barriers.
• Revolutionize IBD treatment, reduce disease relapse and avoid complications.