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Serotonin 2B Receptor Antagonism to Prevent Heart Valve Disease
Overview of Clinical Problem
Age-related heart valve disease is the 3rd leading cause of cardiovascular disease (~20,000 deaths per year in US)
Degenerative aortic valve disease (DAVD) affects over 25% of people over 65 years of age
Only effective long-term treatment for advanced DAVD is invasive, high-risk valve replacement surgery
Non-invasive therapeutic to stop the development/progression of DAVD would greatly benefit those most at risk for developing severe DAVD
Epidemiological studies have revealed that once promising drug candidates have not proven successful at slowing or reversing the end stages of DAVD that necessitate valve replacement
There is no pharmacological strategy currently in development that has the potential to prevent DAVD
Vanderbilt researchers have developed a novel approach that could potentially prevent or slow the progression of DAVD at its earliest possible stages so as to greatly increase patient quality of life. The initial mechanism which triggers fibrotic lesion formation occurs by phenotypic modulation of the aortic valve interstitial cells (AVICs) to the constitutive myofibroblast phenotype, producing significant amounts of extracellular matrix, similar to fibrotic remodeling in other tissues. Thus, desired goal to prevent DAVD is to control the phenotype modulation by specifically inhibiting molecular mechanisms that are known to cause activation of AVICs. This is achieved by inhibiting transforming growth factor-β1 (TGF-β1) activity via the antagonism of two specific G protein-coupled receptors (GPCRs) that are found on AVICs, serotonin 2B receptor (5-HT2B) and angiotensin II type I receptor (AT1R). Preliminary results demonstrate the ‘proof-of-concept’ that 5-HT2BR and TGF- β1 pathways are intermingled, and that inhibiting TGF-β1 signaling to prevent AVICs from becoming activated myofibroblasts is possible with a 5-HT2BR antagonist. If this strategy is systematically examined and found to be effective, it presents a possible pharmacological approach to preventing DAVD.
Intellectual Property Status
U.S. Patent application is being filed for this technology.