The first grant of the Dangoor Center for Personalized Medicine has been awarded to a project using innovative epigenetic methods in order to enhance diagnosis and treatment of patients with acute coronary disease.
Cardiovascular diseases are defined by the patient’s loss of flexibility in his or her blood vessels or his or her obstructed and diminished blood flow. This class of diseases is the #1 cause of death in the western world, accounting for one in three deaths in Israel and one in four deaths in the UK and in the US, and a large proportion of pre-mature deaths.
Cardiovascular diseases include acute coronary syndrome, other heart events, stroke, diabetes and metabolic syndrome, and kidney failure. In all of these diseases, a vital organ or tissue, such as the heart muscle, brain, or kidney, fails to receive nutrition and oxygen; and in all, there is a process of escalating inflammation leading to final collapse and a threat to life.
Associated with cardiovascular disease is atherosclerotic plaque. This plaque—which is made up of fat, cholesterol, calcium, and other substances— is present in all people, but in some people it accumulates in greater amounts on the inner surfaces of arteries. Too much accumulation obstructs blood flow to the limbs and can result in ischemia and consequently organ failure and death. Sudden rupture of accumulated plaque with its subsequent avalanche of debris can clog arteries and lead to acute ischemia, acute cardiac infarction, and stroke—which in a matter of minutes can lead to the loss of a limb, of heart function, and of parts of the brain essential for higher level cognition. And too often it results in death.
One central mystery of medicine is why some plaques are especially prone to rupture. Understanding how plaques develop and how they rupture is crucial for treating and preventing these tragedies. Ostensibly, the reason for plaque formation, as well as its content and clinical course of events, differ from one patient to another, and recognizing that coulad vastly improve medical management. Dangoor Center researchers are now working to do precisely that.
Plaque does not act on its own. Platelets, white cells sub-type, specific lipoproteins are associated with the formation of the thrombin-platelet clot and “angry blood.” Extensive research over more than a century yielded a number of prognostic variables, showing for example that plasma levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with cardiovascular disease. Such findings however have not translated into effective treatments. Increasing HDL-C levels, for example, would be a promising therapeutic strategy. However, recent extensive, closely-watched clinical trials, of three orally-active agents which raise HDL-C levels, all failed. This highlights how little we understand the biology of HDL particles.
The Dangoor Center researchers heading this project hypothesize that the missing link in our understanding of the biological process is a particular group of nucleic acids, mainly micro-RNAs. Some of these nucleic acids would be critical agents in the escalating inflammation that promotes clogging of blood vessels, while others would attenuate inflammatory processes and would therefore be protective of consequent diseases. To explore this hypothesis, they are characterizing the nucleic acids, mainly micro-RNAs, found in the blood, cells, and plaques of participating patients, and seeking statistical relationships between the presence of each micro-RNA and variables which have been shown to predict cardiovascular disease.
Because some of the patients participating in this personalized treatment and research program come from unique and poorly investigated demographic populations, such as the Druze, the Dangoor Center researchers are also investigating the causes of the high rates of cardiovascular disease found in these groups.
Prof. Ofer Amir heads the cardiovascular services at Poria hospital and works with participating patients, while Prof. Haviv and Dr. Karpuj of the School’s Genome Technology center conduct laboratory analysis on our Safed campus. To date, they have analyzed samples from seventy-two patients. Already they have identified novel small RNA species and shown that their presence matches up with the best known diagnostic parameters. They are now working on fractionating the blood of the patients into exosomes and lipid factions and further dividing between LDL and HDL-C in order to further investigate where in the blood this micro-RNA is present.
One major component of this research takes place behind the scenes, where it only just touches the interactions of patients with Dr. Ofer Amir and the wet labs of Prof. Haviv and Dr. Marcela V. Karpuj. It is the development of a database integrating laboratory results and patient outcomes. This database allows the researches to employ “big data” techniques and to share their results in highly useful ways with other researcher-clinician teams around the world.