Gina Shaw, Shaw is a freelance writer based in Montclair, NJ.
Many researchers believe regenerative therapy will change the practice of cardiology as it is now known.
About one million Americans suffer a heart attack every year. While four in ten of them die as a result, that leaves six in ten survivors fighting to recover with permanently damaged heart muscle. Even in the best-case scenarios, cardiologists are usually only able to save about 60% of cardiac muscle after a heart attack. Meanwhile, another five million people are living with heart failure, and another six million visit the emergency room every year for chest pain.
That’s a lot of people with damaged hearts, and up until recently, there was no way to restore that lost heart function. But now, the field of stem cell therapy seems poised to revolutionize the way cardiovascular disease is treated. After years of promising basic science research, stem cell therapy has moved from the lab to the clinic, and early clinical trials hint that stem cells may be able to regenerate damaged heart tissue in humans just as it has been shown to do in animal models.
Within the next few weeks, the National Heart, Lung and Blood Institute is expected to announce the recipients of a total of $33 million in grants to create a national Cardiovascular Cell Therapy Research Network. Five clinical centers, plus one data coordinating center, will focus on evaluating “novel cell therapy treatment strategies for individuals with cardiovascular disease.” By “cell therapy,” the NHLBI does not mean the embryonic kind. That research is, of course, largely barred from federal funding and, when it comes to cardiovascular disease, very much in its earliest phases even in the few US and foreign laboratories pursuing it.
“There are a couple of labs studying cardiogenesis using embryonic stem cell models, but practical and ethical issues have put a damper on that work,” says Eduardo Marban, MD, PhD, chief of cardiology and director of the Donald W. Reynolds Cardiovascular Clinical Research Center at Johns Hopkins University, Baltimore. “Without therapeutic cloning, these cells can lead to immune rejection, and if you’re not careful and lucky they can produce benign tumors in the heart. For those reasons, embryonic stem cell therapy hasn’t been particularly promising in cardiology, at least in the short term, although if those issues are overcome, that could change.”
Several kinds of adult stem cells have already shown promise in both animal and human models of heart disease. Just how much promise, exactly how they work, and how they should be used in real-world treatment scenarios are all questions that remain to be answered.
Bred in the bone
The September 21 edition of the New England Journal of Medicine featured the results of the largest clinical study of cardiac cell therapy yet, the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial. It studied the direct intracoronary infusion of bone marrow progenitor cells in patients who had been successfully treated for acute myocardial infarction. The double-blind trial found a small but definite improvement in left ventricular ejection fraction (LVEF), 5.5% vs. 3%, in the patients who received the bone marrow stem cells, and those patients had a significantly lower rate of adverse events after one year than the placebo patients. Still, the difference was small, and another trial published in the same issue, the smaller Autologous Stem-Cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial, found no improvement in LVEF. Is this really so promising?
Marban thinks it is—for more than one reason. “The bottom line is what these studies tell us about delivery. It appears to be safe to deliver cells down the coronary tree, which opens up the possibility of the use of cell therapy in a big way. Almost every hospital has a cath lab,” he says. “In addition, most of the patients in the REPAIR-AMI trial had pretty normal ejection fraction, and it’s hard to improve when patients have 50% or better EF. In a subgroup analysis, patients with less than 50% EF had a higher proportional benefit. I think it’s fair to say that the studies show that the general approach of coronary delivery of cells can be safe, and the benefit from bone marrow mononuclear cells is modest, but probably genuine.”
That modest rate of recovery may be because bone marrow cells don’t actually turn into cardiomyocytes. Although scientists are still not 100% certain about precisely what happens when bone marrow progenitor cells are delivered to an injured heart, the prevailing wisdom is that they seem to be “biocatalysts to promote healing and recovery of cardiac function,” says Douglas Vaughan, MD, chief of the Division of Cardiovascular Medicine at Vanderbilt University Medical Center, Nashville, Tenn. The division has begun enrolling patients in a small phase I trial of hematopoietic CD34+-enriched bone marrow-derived cells for treatment after heart attack. The study will ultimately enroll 60 patients who must have been scheduled for coronary artery bypass and have decreased ventricular function.
“These cells are probably just small bioreactors. You put them into a certain environment, and they look at what’s going on in the environment and start producing whatever growth factors or other chemicals are required,” says Amit Patel, MD, director of cardiac stem cell therapies at The McGowan Institute for Regenerative Medicine at the University of Pittsburgh Medical Center. Patel, a pioneer in the field, famously treated Hawaiian singer Don Ho for nonischemic cardiomyopathy in Thailand last December using Ho’s own blood-derived stem cells.
“If they’re in an area where there’s enough blood supply but the muscle is weak, the cells appear to secrete substances that will recruit factors that will help the muscle work better or stronger,” he says. “If the muscle is strong but lacks adequate blood supply, they will recruit factors that cause angiogenesis. They put out the equivalent of one of those $2 million, 30-second Super Bowl ads: ‘Hey, we have this super job, we’re going to recruit everyone.'”
Both the REPAIR-AMI and ASTAMI trials were phase I, as is the Vanderbilt trial. In March, Baxter Healthcare Corporation announced it had initiated the first human phase II adult stem cell therapy trial in the US, investigating the potential of CD34+ stem cells in patients with chronic myocardial ischemia (CMI), a severe form of coronary artery disease which develops in between 125,000 and 250,000 people with coronary artery disease annually. The trial will be led by Douglas Losordo, MD, chief of cardiovascular research at Caritas St. Elizabeth’s Medical Center in Boston.
Another phase II trial should be up and running by early next year, run by a small Ohio-based company called Arteriocyte spun off from Case Western Reserve University in Cleveland. “They’re using CD133+ bone marrow cells, which are very similar to CD34+ cells, almost like cousins. They’re both hematopoeitic, and the way you isolate them is the same,” says Patel.
The heart’s own stem cells
Until about three years ago, the received wisdom of cardiology was that everyone is born with a finite number of cardiac cells. The heart grows larger as people age because the cells enlarge, but one can’t grow new heart cells. That dogma was turned on its ear with the discovery of cardiac stem cells. In 2004 and 2005, scientists at several institutions—New York Medical College in Valhalla, and later Baylor College of Medicine in Houston and the University of California at San Diego—identified niches of progenitor cells in the postnatal heart in humans as well as animals.
If they already have their own personal reservoirs of custom stem cells, why don’t our hearts repair themselves naturally? “I think they actually do,” says Patel. “The body may make a strategic choice. When it’s having a heart attack, does it keep fighting the problem, sending a million stem cells to regenerate the area, or wall off the area that is affected and dying? If it walls off that part of the heart, it may preserve the organ and come back to fight another day, but if it keeps stem cells flowing into the area, it might be fighting a losing battle and also lose the war.”
In smaller creatures, the heart possesses the capacity to regenerate itself. “In salamanders and newts, you can cause significant heart injury, but then things slow or stop for awhile and then reverse the scarring,” says Patel. “We haven’t figured out how to do that in ‘grown-ups’ yet. There just aren’t enough stem cells.”
But what if they could be coaxed to multiply? They can. Scientists, including Marban, have extracted cardiac stem cells from patients undergoing cardiac biopsies, and watched them multiply and generate beating cardiospheres that “began to look like little hearts in a dish.” Tested in mice and pigs, the cardiac stem cells appear to regenerate cardiac tissue and restore pumping capacity. The new cells appear to be able to conduct electricity and contract, just as they would have to do in the human heart. “We can grow millions of cells in a relatively short period of time,” says Marban, who’s now working out the methods for a first human trial of this therapy with large-animal preclinical studies. He expects to start phase I trials within 12 to 18 months.
If successful, the cardiac stem cell approach could pole vault over some of the potential limitations of stem cell therapy. Because they are derived from the patient’s own heart, there is no question of rejection, and they may be less likely to spur the growth of benign or malignant tumors, always a worry with stem cell therapy. “Since cardiac stem cells are already partially differentiated into heart muscle, we can grow them with limited processing. So far we’ve done karyotypes after several passages and the cells are all chromosomally normal,” Marban says.
The technique has its limitations. Marban notes that researchers must watch for the development of dangerous arrhythmias should the heart muscle regrown by stem cells create electrical instability. And because it takes about three weeks to generate a suitable population of new stem cells, it’s not likely to be used in patients in the throes of a heart attack or immediately afterward. Bone marrow cells may hold more promise for emergency therapy.
But for the millions of people with heart failure, cardiac stem cell therapy may offer tremendous potential as a long-term treatment, enough that a Maryland biotech firm called Capricor Inc., has already licensed some key patents from Hopkins and has begun trying to develop the technology commercially. “There’s something special about them. They’re already within the heart and evolved to repair wear and tear. If we’re lucky and clever enough, we can harness their regenerative potential and shift the balance toward regrowth rather than fibrosis,” Marban says.
Another potential option for cardiac stem cell therapy, although one still in a much earlier stage than either bone marrow or cardiac stem cells, is the concept of reprogrammed adult stem cells. PrimeCell Therapeutics LLC, Irvine, Calif., has taken adult stem cells from human testes and reprogrammed them to develop pluripotent capabilities, replicating into a number of other types of cells, including cardiac cells.
“They’re able to create all the same things we’ve seen with other types of stem cell research: beating heart cells, nerve cells that fire electricity, and so on. Those cells show a lot of promise,” says Patel, who’s also working with this type of cell. It, too, has its limitations: it has to be autologous, so at least for the moment, there’s no off-the-shelf option, and obviously stem cells extracted from the testes are only available to men. Patel reports that ovarian cells are being studied for these capabilities as well, but that is in an earlier stage of research. And the perennial conundrum of stem cells, tumor potential, remains. So far, at least some level of tumor growth has occurred in all the reprogrammed testicular adult stem cells.
Heart of the matter
But exactly how does it all work? That’s a critical question about cardiac regeneration using stem cells, and one that scientists don’t yet have the answer to. They have theories, some more popular than others. “If I knew for sure how it works, I’d be on a plane to Sweden. Any time someone will tell you they know exactly what the mechanism is, they’re lying,” Patel says.
“There’s a big need for basic research to find out what’s going on, and that’s where our focus is,” says Edward Yeh, MD, professor and chair of the department of cardiology at the M.D. Anderson Cancer Center in Houston, who is studying the use of blood stem cells to restore damaged hearts. Yeh and his research team, which includes investigators from the Texas Heart Institute, have been looking for a relatively simple way to help restore the function of hearts damaged by chemotherapy. “Deriving stem cells from bone marrow is a complicated matter. It would be much easier for patients if the stem cells were taken from blood,” he says.
Yeh is studying CD34+ mobilized cells. “At the moment our conclusion is that these cells can turn into muscle cells, but not directly.” Instead, he says, through a process of cell fusion, the CD34+ cells appear to fuse with resident cardiac myocytes at the border zone of the injury to the heart, where the cells are damaged but not dead and blood supply remains. “This is where the action is. They appear to fuse and create a new cell type, which looks like cardiac cells, and these cells can divide for up to a couple of months in our mouse studies.”
Yeh’s team has also found they can manipulate the “cell fusion” process to create blood vessel-forming cells instead. “By using antibodies to block either fusion or angiogenesis, we can make the system give us either or both,” he says. Yeh adds that they are now trying to use magnetic resonance imaging to follow the animals long-term to see what happens. They suspect that both myogenesis and angiogenesis, as well as a paracrine factor, the biocatalyst function described earlier, are all needed to make this work. “That’s the best we know at this point.”
Scientists at the Cooper Heart Institute and the Coriell Institute for Medical Research in Camden, N.J., are collaborating on a project funded through a $300,000 grant from the New Jersey Commission on Science and Technology. The goal of the project is to use human mesenchymal stem cells derived from cord blood to understand the molecular mechanisms involved in the remodeling of cardiac tissue after myocardial damage.
“We expose the cardiac myocyte to an ischemic reperfusion injury by putting the cells in a lab incubator that has low oxygen,” says Biaggio Saitta, PhD, associate professor in the stem cell and matrix biology laboratory at Coriell and at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School. “Then, in culture, we expose the isolated cord blood mesenchymal stem cells to the injured myocytes or cardiac fibroblasts.”
The New Jersey team is studying the proteins and growth factors that are released by the injured cardiac cells and how these factors stimulate the adjacent mesenchymal stem cells in culture. They use a transwell membrane with micropores that will not allow the cells to touch, but will allow them to secrete factors that will be exposed to other cells. “We want to understand which proteins within the extracellular matrix are involved in the remodeling of the cardiac cells after infarction, what molecular pathways are involved in this remodeling of the cells and eventually create scarring and fibrosis, and how these proteins and factors can affect the function of the mesenchymal stem cells toward cardiac remodeling.”
However the process works, early clinical indications are that stem cell therapy can be revolutionary for some patients. “There are people with chest pain who have gone from chest pain to no chest pain at all,” says Patel. “In randomized trials in Europe, 70% to 80% of people got better. Even in Doug Losordo’s phase I safety trial, he was able to show that some people became chest-pain free. Are all patients who get stem cells going to get better? No. Just like with any other therapy, you have to select your patients correctly, and we’re continually refining which patients may benefit.” For example, he notes, diseases like diabetes, kidney failure, and liver failure, which often accompany cardiovascular disease, can have a dramatic impact on a patient’s stem cells.
The field must be approached with caution, Marban says. “Right now, it’s a little bit of the Wild Wild West out there, and there’s a lot of hucksterism. It’s hard to know what to believe and what not to. But I’m very bullish on this. I think the field of regenerative therapy will change the practice of cardiology as we know it.”
This article was published in Drug Discovery & Development magazine: Vol. 9, No. 11, November, 2006, pp. 20-26.
Filed Under: Drug Discovery