Mucosal Thrombin Inhibition for IBD Treatment
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Solution Overview
Problem
Current therapeutic approaches for inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis primarily target inflammatory cell infiltration, while increased serine protease activity, particularly thrombin, contributes to tissue dysfunction and inflammation, with existing treatments like heparin showing counter-intuitive benefits, highlighting the need for a targeted mechanism to address mucosal thrombin's pro-inflammatory role.
Innovation Solution
A direct thrombin inhibitor is administered locally in the gut to inhibit mucosal thrombin activity, using recombinant food-grade bacteria expressing serpin family proteins like AntiThrombin, Heparin Cofactor II, or protease Nexin 1 to specifically target and reduce thrombin-induced inflammation and bacterial virulence in IBD patients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If heparin (indirect thrombin inhibitor) is administered to IBD patients, then some therapeutic benefits are observed, but the treatment is counter-intuitive given thrombin's pro-coagulant role and patients' mucosal bleeding
Solution Approach 1:
The patent applies this principle by converting thrombin's harmful pro-inflammatory and pro-coagulant effects into a therapeutic target. By using direct thrombin inhibitors to block thrombin's pathogenic actions while preserving necessary physiological functions, the treatment transforms the understanding of thrombin from a protective factor to a disease driver, thereby converting the harmful role into a treatable target
Solution Approach 2:
The patent changes the parameter of thrombin inhibition from indirect (heparin) to direct (DTIs like dabigatran, argatroban, or hirudin), altering the mechanism of action to achieve more specific and predictable inhibition of thrombin's pro-inflammatory effects on mucosal tissue without the counter-intuitive complications of indirect inhibition
2Reliability
If current therapeutic approaches targeting inflammatory cell infiltration are used, then immune system overactivation is addressed, but mucosal thrombin-induced tissue dysfunction and inflammation are not adequately treated
Solution Approach 1:
The patent segments the inflammatory pathway into distinct components: immune cell infiltration (addressed by current therapies) and thrombin-mediated tissue dysfunction (addressed by the new invention). By targeting thrombin specifically, the treatment addresses a separate but complementary pathogenic mechanism, thereby expanding treatment coverage without interfering with existing immunomodulatory approaches
Solution Approach 2:
The patent applies universality by using direct thrombin inhibitors that simultaneously address multiple pathogenic mechanisms: they inhibit thrombin's pro-coagulant effects, block pro-inflammatory signaling through PAR receptors, and reduce tissue dysfunction. This single intervention targets multiple aspects of IBD pathogenesis, making the treatment versatile across different disease manifestations
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The local administration of direct thrombin inhibitors significantly decreases inflammatory parameters, including fecal bleeding scores, and reduces mucosal damage, offering a new therapeutic approach by targeting the pro-inflammatory effects of thrombin in IBD, potentially leading to complete depletion of pathological features.
Implementation Method 1
a recombinant food-grade bacterium comprising a gene selected from a gene coding for a member of the serpin family proteins or an active fraction of a member of the serpin family proteins (AntiThrombin, Heparin Cofactor II, Protein C inhibitor and protease Nexin 1) for use in the treatment of a patient affected with an inflammatory bowel disease
Data Source
AI summary
Inventor's general objective was to investigate the potential role of mucosal thrombin in intestinal inflammation and its mechanisms of action. First, they evaluated whether there is an increased presence of active thrombin in Crohn's Disease (CD): both in patient tissues and in an animal models of IBD. Second, they investigated the effects on mucosal damage and tissue dysfunction resulting from the intracolonic administration of thrombin at a dose comparable to what was detected in the tissue of CD patients. Third, they demonstrated in IBD mouse model that pharmacological inhibition of mucosal thrombin activity is a new therapeutic approach to this debilitating condition, such inhibition, allows to significantly decrease all inflammatory parameters including the fecal bleeding score. Finally, inventors showed that human mucosa-associated commensal biofilms exposed to increasing concentrations of human thrombin exhibited increase in their virulent properties specifically, increased bacterial invasion into human epithelial cell line). So, the present invention relates to a method for preventing or treating inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) by targeting locally the mucosal Thrombin.