Can gene therapy cure heart disease?

If we know how to take advantage of the self-healing properties of the heart, we may be able to prevent heart attacks and relieve the pain that accompanies severe narrowing of the coronary arteries

By Gabor Rubani, the article is published with the approval of Scientific American Israel and the Ort Israel network 16.02.2017

• The heart has the ability to grow replacement blood vessels when it is in distress. This system of parallel blood vessels, as they are called, can mean the difference between life and death in the event of a heart attack, as it opens up new pathways for blood to flow to damaged areas of the heart muscle.
• For reasons that are not yet clear enough, most heart patients are unable to develop a sufficiently efficient parallel circulatory system.
• Researchers are looking at gene therapy and cell therapy as a means of encouraging the formation of new blood vessels in the heart. If these trials are crowned with success, the innovative treatments will be able to relieve many who suffer from angina pectoris and even prevent heart attacks.

The human heart beats continuously, more than 100,000 times a day, during which it pumps about 7,500 liters of oxygen-rich blood through the aorta to all parts of the body. About 5% of the infused blood reaches two main blood vessels, the coronary arteries, which route it to a branched network of smaller and smaller blood vessels that in turn feed each and every one of the heart muscle fibers.

Sometimes some factor, such as a blood clot or the accumulation of a fatty substance (Atherosclerotic plaque) on the walls of the arteries, blocking the flow of blood in one or more places along the coronary arteries. In such cases, the blockage prevents the passage of oxygen and nutrients to the nearby heart cells. Without rapid resumption of blood flow, the oxygen-hungry part of the heart muscle dies and the result is a heart attack. The more extensive the extent of the damage, the more severe the damage to the heart's function and in extreme cases, the heart may even stop functioning completely, and this means death.

Since a lack of oxygen does not cause the immediate death of heart muscle cells, doctors can still save a significant portion of the cells if they rush the patient to the hospital without delay, before irreversible damage occurs. Among other things, doctors can open arteries that have been created [and blocked to the passage of blood] through insertion Tumchen (stent) to the blocked artery or in bypass surgery, which allows bypassing the blocked part of the artery. These medical procedures are also used to try and prevent heart attacks in advance as well as to relieve pain (Angina) which is often accompanied by a severe narrowing of the arteries, but they do not always achieve their goal and in some cases they even cause new problems.

In fact, the heart has its own ways of dealing with blockages in the coronary arteries. The heart can create new paths, called - Parallel blood vessels, which redirect the blood flow and flow blood from several new directions to areas of the heart muscle suffering from a lack of oxygen. Parallel blood vessels are present in the human body from birth, but usually they do not transport blood. These blood vessels grow and come into action, and can even form anew, only following a blockage or severe narrowing of the coronary arteries. However, this happens only a few weeks after a blockage has occurred. When the parallel vascular system is sufficiently developed, the blood flow through it may be sufficient for nutrition heart tissues even in the case of complete blockage of blood vessels. But all too often, the natural parallel circulatory system is not up to the task.

For two decades, researchers, including the writer of these lines, have been trying to find ways to spur the heart to create parallel blood vessels that can flow blood in sufficient quantity to the heart muscle fibers when they do not receive enough oxygen. In this way, we hope to relieve the oppressive pain for patients suffering fromAtherosclerosis and to prevent heart attacks in cases where it is not possible to use stents or bypass surgery. Until now, our efforts, which included, among other things, the injection of proteins, genes and cells into the heart, have not yielded a drug effective enough to help most of those suffering from severe narrowing of the arteries. However, over the past few years, these procedures have been dramatically refined in experiments conducted by researchers in academia and pharmaceutical industry laboratories. Some of these procedures are currently used in human clinical trials, and their completion is expected in the near future.

If indeed the experiments are crowned with success, the first to benefit from this will be patients suffering from angina pectoris that occurs during exertion or physical activity. This phenomenon is manifested when the coronary arteries that have been damaged due to atherosclerosis can no longer supply all the necessary amount of oxygen to the heart tissues. For various reasons, standard treatments using drugs, stents, or surgery cannot help the several million people worldwide who suffer from angina, approximately 850,000 of whom live in the United States, according to an estimate. An innovative treatment under development is expected to alleviate the symptoms of the disease and improve the quality of life beyond recognition. Those who suffer from it and even allow many who were confined to their homes until now to go out and walk freely in the environment. Such treatment may also prevent a first heart attack or repeated heart attacks at least among some from the patient population.

Parallel blood vessel formation

The first step towards developing a treatment that will encourage the growth and development of new blood vessels in the heart is deciphering the natural mechanism that causes the formation and maturation of parallel blood vessels. For years, researchers have tried to answer the question of which of two factors spurs congenital parallel blood vessels to become medium-sized arteries: is increased blood flow in the parallel blood vessels or a decrease in oxygen supply to a diseased heart muscle? Any of these conditions may be caused by a severe narrowing of a coronary artery. The internal pressure in the artery in the area beyond the point of obstruction decreases since the amount of blood that the created path can flow through is small. This drop in pressure disturbs the balance in the system and as a result, blood is pumped from other areas of the heart that were not damaged to the corresponding blood vessels "downstream". At the same time, the heart tissue beyond the product segment in the artery receives less oxygen due to the decrease in the amount of blood supplied to it. In some of the studies conducted on the subject, evidence was found to support the explanation of increased blood flow in the parallel blood vessels; Other studies point to the decrease in oxygen levels as the cause of the expansion of the congenital parallel vascular system.

The popular explanation today is that both processes together play an important role in the development of the parallel circulatory system in the human heart. The blood that is redirected to the replacement blood vessels is created shear forces The causes of protein release, the so-called growth factors, from the inner lining of the blood vessels, and these in turn stabilize the walls of the arteries and expand their inner diameter. As a result, the arteries that have grown and matured allow for increased blood flow. At the same time, the lack of oxygen in the heart muscle stimulates the release of other growth factors, which encourage the formation of new parallel blood vessels and these may develop into small arteries.

An innovative treatment is expected to relieve the symptoms of angina pectoris and improve the quality of life of many of the patients beyond recognition.

In studies conducted over the past 15 years, it was found that only 20% to 30% of heart patients have a well-developed parallel blood system. It is still not clear why among the majority of patients bCoronary heart disease The corresponding circulatory system does not develop sufficiently to successfully meet the task of bypassing the blockages in the coronary arteries. Studies conducted on the subject indicate that high cholesterol levels in the blood and the damage caused to small blood vessels due to diabetes are two of the main factors that may impair the development of the parallel blood vessels and their function.

An efficient system of parallel blood vessels in the heart can mean the difference between life and death. In a study conducted among 845 heart patients whose condition was serious, the findings of which were published online in 2013, showed Christian Seiler From the University Hospital in Bern in Switzerland and his colleagues that when the parallel blood system of the patients can supply at least 25% of the blood that flowed through the coronary arteries before the disease, their chances of dying from a heart attack during ten years were 67% lower.

research challenges

Studies conducted in recent years point to only one proven method for stimulating the parallel blood circulation in the heart: long-term physical activity, which spurs the heart to function at a higher level than it was used to. A study conducted in Germany among 60 men who suffered from severe coronary heart disease, and its findings were published in 2016, shows thatHigh intensity physical activity For ten hours a week, during one month, or moderate-intensity activity for 15 hours a week, increased blood flow in the corresponding circulatory system of the patients by approximately 40%. In the medium intensity group, the study participants performed six to eight sets of activity per day, at an effort level of 60% of the maximum effort they are able to exert without feeling chest pain. In the high intensity group, the participants in the study performed four sets of activity per day at an effort level of 95% (in which some of them sometimes felt chest pain). The entire activity was conducted under the supervision of experienced doctors and personal fitness trainers. The 40% improvement in the function of the parallel circulatory system is probably the maximum improvement that can be expected considering what is physiologically possible, and this, based on laboratory studies on dogs, from which it appears that the parallel circulation can replace about a third of the blood circulation passing through the coronary arteries.

It is likely that the increased physical activity of the participants in the study increased the pressure in the coronary arteries, which flowed the blood further to the parallel blood vessels. The regular daily training accelerated the expansion and thickening of the blood vessel walls, allowing more blood to flow through them. It is not clear whether the exercise routine also encouraged the development of new parallel blood vessels, since such vessels, even if formed, were still too small at that initial stage to be discernible using Angiography, a type of x-ray scan used to image the coronary arteries.

But for many of the heart patients whose condition is serious even moderate physical activity is not a solution. Therefore, the researchers are trying to develop a drug, based on an optimal combination of engineered proteins, genes and cells, that will stimulate the heart to expand its corresponding blood system.

Some of the early research in this area focused on two different proteins, known by their initials, VEGF and-FGF, which encourage the growth of blood vessels. Initial small-scale studies conducted on various growth factors seemed promising, but follow-up studies conducted among a larger group of patients encountered quite a few difficulties. The main problem that arose was the need to give patients large amounts of proteins for a long period of time in order to create new blood vessels in the heart. On the other hand, the effect of the treatment on other parts of the circulatory system that feed other organs in the body was negative. The treatment caused a drop in blood pressure, sometimes, even severely, and this necessitated the discontinuation of the experimental treatments.

In an attempt to circumvent the problems caused by the use of proteins, some researchers are looking at an alternative way: Gene therapy. The idea is to inject into the heart cells genes that contain molecular "instructions" for creating VEGF, FGF or other proteins directly in the heart. Usually, this is done by inserting the genes into a relatively benign virus that infects the heart cells. If successfully implanted, the genes can initiate an accelerated production process of the necessary growth factors, over time and exactly where they are needed. In experiments conducted on laboratory animals, scientists succeeded in causing the formation and maturation of parallel blood vessels in the heart, but so far no similar success has been recorded in large-scale clinical trials of gene therapy conducted in humans. The failure may be due to the fact that the injected genes did not reach a large enough number of heart muscle cells. And for the sake of full disclosure: the company I own, Angionetics, is trying to develop a similar method for gene therapy, based on the gene that encourages the creation of FGF. In the studies we conducted, we found another way, which may be more effective, to introduce the genetic material into a larger area of ​​the heart, which is essential for creating enough new parallel blood vessels. The American Food and Drug Administration (FDA) granted us permission, in September 2016, to conduct advanced clinical trials of the product we developed in a group of 320 people.

Another group of researchers is trying to examine whether Stem cells Adults taken from the patient's own bone marrow or blood can stimulate a diseased heart to develop new blood vessels. The rationale behind this approach is that stem cells can generate a variety of growth factors, and apparently a variety of growth factors, in carefully measured combinations, are required to generate the necessary number of parallel blood vessels. One of the problems with this process is that it is not always easy to identify how many of the cells injected into the heart continue to function. However, some small-scale clinical trials conducted over the past ten years have produced encouraging findings. Among other things, patients who were exposed to the treatment were able to exercise on a treadmill without feeling pain for a few minutes longer than patients who did not receive the treatment. But, similar to the methods of protein injection and gene therapy, the cellular therapy, using stem cells, has so far not been found to be significantly effective in large-scale clinical trials.

The lessons we learned

Although, it seems that after twenty years of research, we should have already found a large-scale effective solution to create parallel blood vessels in the heart or, alternatively, give up and give up. But everything that my colleagues and I have learned in this field so far confirms our hypothesis that it is possible to stimulate the development of the parallel circulatory system and that this will be of benefit to many. What we must do now is to examine with a comprehensive view all the insights that emerge from the studies we have conducted so far and apply them in a more systematic way to any new initiative in the field.

For example, today we are better at understanding in which way potential drugs should be injected into the heart to achieve an optimal result. In previous experiments, the researchers would inject their preferred experimental drug in one of three ways: directly into the heart muscle, in which case the drug spread to the nearby area, between the muscle fibers; through a vein in the heart, with the drug being pushed back against the blood flow; or through a coronary artery, through which the drug is carried with the blood flow. Some recent studies show that only by injecting the experimental drugs into one or more of the coronary arteries is it possible to reach the existing parallel blood vessels and at the same time encourage the formation of new systems of parallel blood vessels. The existing parallel blood vessels are so distant from the injection sites in the heart muscle or veins that it is impossible to benefit from the treatment. We also learned that temporarily blocking the blood circulation by inflating a small balloon inside the artery while injecting the drugs increases the permeability of the blood vessel walls and allows a larger dose of the drug to reach the heart.

Moreover, in order to prove that treatment can indeed lead to the formation of effective parallel blood vessels in humans, we must make sure that in our clinical trials we are treating those who are suitable for treatment, and this is not an easy challenge. Most likely, drugs designed to expand existing parallel blood vessels and create new parallel blood vessels will not improve the condition of the 20% to 30% of heart patients whose parallel blood system is already well developed. Including them in our experimental studies, they will probably not see an improvement in their condition, will cause the research findings to be distorted and reduce the benefit of the treatment for the others. Weighing the findings of this group, which actually does not need this treatment, with the findings of the other participants in the experiment will present a distorted picture of findings that are less successful than they really are and will lead to the erroneous conclusion that the treatment has failed.

Until now, the most accurate method for measuring the parallel blood circulation was to insert a small balloon through a catheter into a coronary artery, inflating the balloon to block the passage of blood in the artery for a short time and measuring the amount of blood that flows in a bypass, presumably through the parallel blood vessels. But this procedure is too complicated and expensive when the goal is to identify the majority of patients who can benefit from the formation of alternative blood vessels in their heart and to verify the effect of the treatment on them. Less invasive methods for measuring the parallel circulation have also been developed, but for now, they are not accurate enough. We still need to develop a simple standardized method for measuring blood flow in the parallel system so that we can identify suitable candidates for clinical trials and detect treatment success when we achieve it.

In light of these and other lessons that we have learned over many years of research, I believe that we are now on the right path to developing new treatments to stimulate the formation of parallel arteries in the heart. During the next few years, we hope, we will be able to offer a successful alternative to the hundreds of thousands of heart patients for whom an effective cure has not yet been found.

for further reading

• The Collateral Circulation of the Heart. Pascal Meier et al. in BMC Medicine, Vol. 11, Article No. 143. Published online June 4, 2013
• Angiogenic Gene Therapy for Refractory Angina. Gabor M. Rubanyi in Expert Opinion on Biological Therapy, Vol. 16, no. 3, pages 303–315; 2015
• Coronary Collateral Growth Induced by Physical Exercise: Results of the Leipzig EXerCIseTraining versus MEdical Management in Patients with Stable Coronary Artery Disease (EXCITE) Trial. Sven Möbius-Winkler et al. in Circulation, Vol. 133, no. 15, pages 1438–1448; April 12, 2016