heartbeat
Cell Therapy for Heart Disease
New gene and stem cell therapies offer promise for heart attack victims.
By Douglas P. Zipes, M.D.
From the May/June 2006 Issue
How can stem cell therapies be used to treat hearts damaged by heart attack or heart failure? Harnessing the next generation of therapies based on stem cells is the intense focus of leading researchers at Johns Hopkins School of Medicine.Dr. Zipes: How do genes work? What do they do? Eduardo: Genes are the blueprints for inheritance and for the creation of all body parts. Located on chromosomes in the nucleus of every cell in the body, genes encode the material passed from one generation to another. Specifically, each gene contains the information necessary to create a particular protein—the actual building blocks of tissues.Dr. Zipes: Every cell possesses the genes sufficient to create an individual? Eduardo: That's right. Each cell in the body contains a copy of the entire genetic material. What makes adult cells different from each other has to do with the complement or repertoire of genes that is being expressed at any given time in that cell. It's the combination or particular orchestration of genes that any given cell or tissue expresses which makes it unique. But every cell has the genetic material capable of basically producing the entire code that makes an individual an individual.Dr. Zipes: If there is an abnormal gene or abnormal functioning of a gene, how can one modulate that function? Eduardo: In a number of disorders, a particular gene is either missing or deficient or conversely expressed too intensely. Both processes occur in human disease. If a particular gene is missing or deficient, you can think about using targeted overexpression of a gene—meaning delivering extra copies of the gene to the cell, using what we call a "vector." A vector is a delivery vehicle that carries DNA into a cell to either more intensely express a gene that is deficient or using one of various molecular tricks to suppress the function of a gene too strongly expressed in a cell or tissue. Dr. Zipes: Can medications alter or modulate gene function? Eduardo: Yes. One way of influencing gene expression without using gene therapy is using drugs or hormones to influence whether a particular gene is turned on or off, or to see whether a gene makes its way to its proper place in the cell. This can be done in various ways using small molecules or drugs. The intervention is not the same as gene therapy where we actually use genetic material, typically DNA, to influence the function of genes.Dr. Zipes: Obviously, gene therapy has been an important focus of research in your lab. Why is this research important, and why would gene therapy be better than, say, drug treatment, surgery, or other therapeutic approaches? Eduardo: One general category of using gene therapy is to correct a deficiency or reverse an excess of a gene product. Another general category is simply to use genes as elements in a toolbox, as it were, to reprogram or alter the function of a tissue toward salutary ends by making tissue work better or more precisely in the situation of disease. Dr. Zipes: Gene therapy, in essence, corrects the abnormality at its source or provides a new source to correct the abnormality, rather than, for example, a patient taking a drug on a daily basis or having electronic equipment implanted. Eduardo: That's right. The idea of functional engineering gene therapy would not necessarily be to correct a deficiency or overexpression of a gene, but rather to take advantage of genes to reprogram cells for different or better purposes. That is exactly what happens when you create, let's say, a biological pacemaker—you achieve a type of biological alchemy by converting the normal behavior of a cell or tissue into a new behavior. In this case, you are basically creating a pacemaker in the heart to replace a deficient pacemaker or malfunctioning electrical system.Dr. Zipes: You mentioned one gene therapy application for abnormal heart rhythms. In what other cardiovascular applications might gene therapy be useful? Eduardo: One area of interest is using genes to promote the growth of new blood vessels in areas of scar or damage surrounding a heart attack with a view to healing the injury by producing better blood flow. We can do this now, employing conventional techniques such as stents and angioplasties. But sometimes the blood vessels are so diseased that the only way we can contemplate getting more blood flow to a heart deficient in blood flow is to create and grow new blood vessels. There is an interest in the idea of injecting genes into damaged heart muscle with inadequate blood flow to increase or stimulate the growth of capillaries and new blood vessels—an area called angiogenesis. Whether or not this process will work, it is hard to tell. Some early clinical trials have been disappointing, but ongoing studies are investigating the potential of angiogenesis not only for the heart itself, but also in peripheral vascular diseases where there is insufficient blood flow to the legs and arms, for example.Dr. Zipes: Would angiogenesis cause the cancer cells to elaborate faster if a person had an undisclosed cancer? Eduardo: There is a fear that if the gene were to escape from the heart and end up in a precancerous cell in the liver, for example, it might stimulate the growth of the cell in the liver into a real tumor. That is one potential downside of therapeutic angiogenesis—leaky expression in other tissues. The other concern is that we can grow new blood vessels, but they might not be very beneficial in providing more oxygen to the tissues because they are too localized or immature. Dr. Zipes: Suppose one of our readers, for example, has had a heart attack with actual death and scarring of heart muscle. Now, the heart is not working very well and the patient has developed heart failure. Are approaches available that can actually restore new heart cells and heart function in these individuals? Eduardo: The most promising strategies in this case involve not gene therapy per se, but cell therapy—the entire area that we now call regenerative medicine. Some cells used to regrow heart muscle are regular cells, such as bone marrow cells, as well as cells that are relatively immature and capable of perhaps either stimulating the heart muscle to contract better or actually turning into heart muscle. Stem cells are another promising direction.Dr. Zipes: What is a stem cell? Eduardo: A stem cell is an immature cell that is poised and ready with proper stimulation to become any one of several different mature cells. A stem cell is like a utility player on a baseball team, capable of filling any of various positions given the right directives. The truest stem cells are the ones that begin life in the embryo and basically create the entire body—the embryonic stem cells. We are actually much more interested in "here and now" practical therapeutics using adult stem cells, which are derived from tissues within the body and that provide endogenous repair capacity for any given organ.Dr. Zipes: Does every organ—and specifically the heart—have a percentage of these stem cells that over time would essentially regrow the organ and repair damaged cells? Eduardo: The textbooks are being re-written on a daily basis in this rapidly evolving field. It appears that we will be able to identify endogenous stem cells in most, if not all, tissues in the body. Dr. Zipes: That really is an incredible potential advance. How do you harvest the cells from an individual so you can then grow them and reinfuse them into the individual? Eduardo: The challenge lies in the fact that these cells come from the heart, and therefore a little sample of heart muscle must be obtained. There are two ways we do this. One, we can retrieve a sample during cardiac surgery. Two, we use a catheter device to perform a biopsy on the heart through a very small incision in the neck—a so-called endomyocardial biopsy technique. Either method is plausible in terms of harvesting stem cells and using them for autologous repair—at least in animals. To date, this research has been done using biopsies from human hearts and introducing human cells into animals, but not yet human cells into humans. We hope to begin this research within a year.Dr. Zipes: Does using adult stem cells circumvent federal restrictions on using embryonic human stem cells? Eduardo: Cardiac stem cells have many advantages. One, of course, is that there is no moral or ethical dilemma with respect to the creation or destruction of embryos. Autologous cells also are a perfect genetic match. If we can harvest the cells from an individual, grow them up in a laboratory, and reintroduce them into the same individual, there wouldn't be any possibility of rejection. Dr. Zipes: Since the cells occur with such paucity, how do you grow them and separate them from other cells? Eduardo: The processes that we have developed appear capable of doing that, although we are not entirely sure how the cells capable of repairing the heart muscle grow with alacrity in a dish under highly artificial conditions. That is a topic of biologic interest.Dr. Zipes: In itself, that is a fundamentally exciting observation. Do you have some estimate as to how many cells are needed to repair damage? And where do you inject the cells? Eduardo: At this point, we can only guess as to how many cells will be enough and how many will be too much. In principle, we are guided by work done largely in Europe—and increasingly in this country—using bone marrow cells. These are not pure stem cells; they are bone marrow mononuclear cells harvested from adult bone marrow using a needle biopsy and placed back into the hearts of heart attack victims. The cells are reintroduced using routine coronary catheters utilized to perform angioplasties.Dr. Zipes: What are your group's plans in terms of applying these observations to patients who have had scarring from a heart attack or insufficient blood flow to make them better? Eduardo: Our personal goal right now is to complete preclinical studies within the next six months. As soon as that data is available and analyzed, we will seek regulatory approval to begin what we call Phase I clinical studies—safety studies—in a few patients before the end of 2006. Phase I studies typically take six months to one year to complete. If safety can be established, we will do larger studies with hundreds of patients to establish not only whether the therapy is safe, but if it works. Our target is real clinical therapy and studies directed at clinical therapy within the next 12 months. Dr. Zipes: That is amazing. We have talked about the potential benefits. What are some of the potential side effects or downsides of gene and stem cell therapies? Eduardo: There are potential problems. The one that we worry about the most is tumor formation. Whenever you put genes or cells into the body, particularly in places where they weren't necessarily meant to be, you wonder if there is a dark side to genetic reprogramming. We touched upon one such potential risk or danger with regard to gene therapy, specifically in the field of angiogenesis, of turning a latent cancer into an aggressive cancer. Dr. Zipes: What are your concerns about longevity and reliability of the therapy? Perhaps they are a bit less important than the two primary problems you mentioned, but obviously they have to play a role as well. Eduardo: Longevity and reliability are concerns that we have begun to assess. I will note that with some of the early promise in European studies, a benefit has been seen at six months, but it seems to wear off when patients are re-examined one or two years later. In other words, the benefit in terms of increased heart function—evident relatively early after treating with the bone marrow cells—disappears relative to untreated patients when patients are followed for a longer time. Dr. Zipes: Do you see any incredible breakthroughs or major advances emerging? Eduardo: The field is poised for a revolution—one that comes every 10 to 20 years. The last major revolution can be argued to have arrived with the advent of the wonderful devices that we have to treat arrhythmias—implantable cardioverter defibrillators (ICDs) and pacemakers. Another major advance has been in the area of stents and correction of clogged arteries using mechanical means.
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