The National Heart, Lung, and Blood Institute (NHLBI) recently awarded The Texas Heart Institute® (THI) a two-year, $1.14 million grant to develop a novel, first-in-class drug to treat cardiovascular disease (CVD) as a significant improvement to current treatment regimens -; specifically for adverse events arising from atherosclerosis.
Cardiovascular disease is the leading cause of death worldwide, with the Centers for Disease Control and Prevention (CDC) estimating that one person dies from CVD every 33 seconds in the United States, accounting for one in every five deaths in 2021.
CVD leads to heart attack, heart failure, and stroke, mainly caused by atherosclerosis -; the thickening and hardening of arteries, which carry oxygen-rich blood from the heart to the rest of the body -; due to plaque buildup. The plaques, formed by cholesterol deposits and other substances, cause arteries to become narrow, blocking blood flow. The consequent chronic inflammation eventually results in atherosclerotic plaque rupture or erosion, which is the leading cause of adverse cardiac events.
Conventional therapeutic approaches include the use of lipid-lowering statin drugs; however, many patients taking these medications still suffer life-threatening incidents often caused by residual inflammation risks. Indeed, many prominent clinical trials have established that atherosclerosis is an inflammatory disease and that lowering inflammation can reduce adverse cardiac events independent of statin drugs.
Targeting this lingering inflammation -; even in patients currently receiving the best standards of care -; can significantly benefit clinical outcomes.
Given the sobering mortality statistics associated with heart disease, a novel therapy that could change disease trajectory and delay or prevent events associated with atherosclerotic cardiovascular disease would be a significant improvement to current treatment regimens."
Dr. Darren G. Woodside, Vice President for Research, Senior Investigator, and Director of the Flow Cytometry and Imaging Core at The Texas Heart Institute
Apart from lipid-lowering approaches, current treatments for atherosclerosis primarily target risk factors associated with cardiovascular events after plaque rupture. In this project -; funded under the NHLBI Catalyze Program -; this new strategy will enable the suppression of white blood cell activation within atherosclerotic plaques beforehand by inhibiting the production of pro-inflammatory mediators like interleukin-1β (IL-1β).
This initiative may lead to starting points for drug development and help establish industry partnerships -; similar to other programs that have recently arisen from THI scientists' inventions -; involving technologies invented by Dr. Woodside and co-principal investigator Dr. Ronald J. Biediger, Director of Medicinal Chemistry, and other members of the Molecular Cardiology Research Laboratories at The Texas Heart Institute.
Drs. Woodside and Biediger initiated a drug discovery and development program to target the molecular interactions between of a group of cell surface proteins called integrins and an intracellular protein termed Syk, which is important for producing IL-1β. Dr. Woodside's team recently published a study in Frontiers in Immunology indicating that such an interaction between integrins and Syk can be inhibited by small molecule compounds. They foresee that those small molecule compounds can be developed to generate an innovative drug to mitigate residual inflammatory risk in cardiovascular patients -; above and beyond the capability of statin drugs -; improving patients' cardiovascular health. The ideal future drug would be orally available, administered daily and have no significant adverse side effects.
"If successful, our approach would represent a first-in-class therapeutic, as no drugs marketed today take advantage of this specific strategy of targeting integrin signaling through Syk," said Dr. Woodside.
This research is supported by the NHLBI of the National Institutes of Health under Award Number: R61 HL168737. The NHLBI, one of the largest institutes and centers comprising the National Institutes of Health (NIH), "provides global leadership for a research, training, and education program to promote the prevention and treatment of heart, lung, and blood disorders and enhance the health of all individuals so that they can live longer and more fulfilling lives."
The content of this research is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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