A Serbian heart patient named Miroslav Dlacic suffered from a heart attack, and this event thoroughly changed his life. His heart was so damaged that he was too tired to work in his garden or work at his leather-accessories workshop in the city of Belgrade. Like other heart attack suffers, Dlacic, at the age of 71, was sure that the rest of his life would be short, and spent without energy.
However, after prompting from the Serbian hospital where he was treated, he participated in a clinical trial at the Mayo Clinic trial that used stem cells to repair his damaged heart tissue, and the results completely changed his life for the better. Two years after his experimental treatment, Dlacic can walk without it wearing him out. “I am more active, more peppy,” he says. “I feel quite well.”
“It’s a paradigm shift,” says Andre Terzic, M.D., Ph.D., director of Mayo Clinic’s Center for Regenerative Medicine and senior investigator of the stem cell trial. “We are moving from traditional medicine, which addresses the symptoms of disease, to being legitimately able to cure disease.”
The treatment of heart patients has usually involved a series of medications that try to manage the decline a of weak heart. However, a collaboration between European and Mayo Clinic researchers have discovered a new way to repair a damaged heart that actually fixes the damaged tissue.
The procedure pioneered by the Mayo Clinic harvests stem cells from the patient’s bone marrow, and then cultures these cells in the laboratory so that they can become cardiac cells. These cultured cells are then injected into the patient’s heart so that they can regenerate healthy heart tissue.
According to Terzic, this Mayo Clinic study is the first successful demonstration in people of the feasibility and safety of transforming adult stem cells into heart cells.
This study could provide new life for millions of heart patients. According to the World Health Organization, cardiovascular disease is the leading cause of death worldwide. About 5.8 million people in the US alone have heart failure, and this number is growing, according to the National Institutes of Health.
Leukemia and lymphoma (cancers of the blood) have been successfully treated with stem cell transplants. However, using stem cells from another organ to treat the heart is a sizeable challenge.
“In leukemia and lymphoma, the transplanted bone marrow is repairing bone marrow,” Dr. Terzic says. “Here, we are asking something unique of the stem cells — to repair another organ. It’s an anatomical mismatch.”
The inspiration for this experiment can from an observation made in the early 2000s. When stem cells from 11 patients undergoing heart bypass surgery were examined and analyzed, cells from two of the patients had an unusually high expression of particular transcription factors. Transcription factors are proteins that control the flow of genetic information between cells, and these cells expressed transcription factors that are important in the formation of heart muscle cells. From a clinical perspective, these two patients did not appear any different from other patients, but their stem cells seemed to show unique capacity for heart repair.
“That gave us the idea to convert nonreparative stem cells to become reparative,” Dr. Terzic says.
Converting nonreparative stem cells into reparative stem cells that can successfully repair the heart requires a deep understanding of how precisely the human heart develops. This detailed, painstaking work was led by Atta Behfar, M.D., Ph.D., a cardiovascular researcher at Mayo Clinic in Rochester, Minn.
In collaboration with other members of the Terzic research team, Dr. Behfar identified hundreds of proteins involved in the process of heart development (cardiogenesis). This team then identified the proteins that are essential in driving a stem cell to become a cardiac cell.
By using computer models, they simulated the effects of eliminating specific proteins one by one from the process of heart development. That method yielded about 25 proteins, but the team was able to reduce this number down to 8 proteins that their data indicated were essential for heart development.
The research team was able to use these proteins to reprogram stem cells to become heart cells. The treated stem cells were dubbed cardiopoietic, or heart creative cells.
This team then used their cardiopoietic cells in a proof-of-principle study that was published in the Journal of the American College of Cardiology in 2010 and demonstrated in laboratory animal models with heart disease that the injection of cardiopoietic cells had improved heart function compared with animals injected with untreated stem cells. This work was proclaimed as a “landmark work,” by the journal’s editorial writer, since this study demonstrated that it was indeed possible to reprogram stem cells to become cardiac cells.
However, the step between laboratory tests and clinical trials is a huge one. The first hurdle is expanding stem cells in the laboratory so that there are enough cells for patient treatments. To solve this problem, the Mayo Clinch team needed collaborators with expertise in expanding stem cells in the laboratory for clinical purposes. To this end, they contacted Cardio3 Biosciences, a bioscience company in Mont-Saint-Guibert, Belgium. Dr. Behfar went to Belgium and spent several months working with scientists at Cardio3.
“The interaction with Cardio3 was crucial to driving Mayo Clinic’s technology forward,” he says.
With these record of laboratory successes, Mayo Clinic applied to European regulatory agencies to conduct a clinical trial to test their cardiopoietic cells in human heart patients. Why did they choose Europe as the setting for their first clinical trials? Practically speaking, it is easier to acquire approval for clinical studies in Europe compared with the United States. However, clinical trials will be held in the U.S. eventually, but Terzic has many previous collaborators at European medical centers who are ready to collaborate with him in this study. Additionally, Cardio3 has a long history of coordinating trials in multiple countries.
The clinical trials involved 45 patients from Belgium, Switzerland and Serbia. All of the patients, including Miroslav Dlacic, experienced heart failure as a result of heart attacks.
Each of these patients were randomly assigned to a group that received cardiopoietic cells or to a control group that received standard care for heart failure. This study examined the safety and feasibility of their procedure, but it should also lead to larger, multiple-site trials.
The results from this initial trial were significant. Stem cells from each patient in the cardiopoiesis group were successfully guided to become cardiac cells. The treated cells were injected into the heart wall of each of those patients without apparent complications.
“It’s critical that this new process of cardiopoiesis was achieved in 100 percent of cases, with a very good safety profile,” Dr. Terzic says. “We have demonstrated the feasibility and safety of this procedure.”
This initial clinical trial wasn’t designed to assess the procedure’s effectiveness, but the early indications are hopeful. If you consider that a failing heart pumps less blood and eventually enlarge, then improvements six months after the cardiopoietic treatment are potentially indicative of increased heart regeneration.
In this study, when examined six months after stem cell therapy, every patient in the cardiopoiesis group had increased blood flow from the heart to the rest of the body, and showed decreased heart volume, all indicators of improved heart health. Patients from the cardiopoietic group were also able to walk longer distances than they could before treatment — on average. By comparison, the 10 patients in the control group showed no change or even deterioration in these measures.
“This preliminary study was not designed to be definitive. But already at six months, there was a significant benefit for patients,” Dr. Terzic says.
Although such data is far from definitive, anecdotal evidence of improvement over the study’s two-year follow-up period came from one patient who was unable to summon sufficient breath to play his trumpet before the experimental treatment but now can do so, and from another who has resumed riding a bicycle.
“We are enabling the heart to regain its initial structure and function,” Dr. Terzic says, “and we will not stop here.”
The clinical trial findings were published in the Journal of the American College of Cardiology in 2013.
Meanwhile, research to improve the injection process and cell effectiveness is underway.
“We are working on novel delivery tools that dramatically increase the cardiopoiresis cells retained by the heart,” Dr. Behfar says. “We have technology and know-how about these stem cells that we couldn’t even have dreamed of 10 years ago when this work began.”
Multicenter, phase III clinical trials are being planned for larger groups in European centers, which will hopefully be followed by trials in the U.S. Unfortunately, much more information is needed before this technique can be validated and approved for regular clinical use.
Mayo Clinic is uniquely positioned to pursue this complex therapy. In addition to its global reach, its Center for Regenerative Medicine is at the forefront of efforts to develop reparative solutions for a range of conditions besides heart disease.
“With the cardiopoiesis research, we have shown that regenerative medicine can really work,” Dr. Terzic says. “We are now actively working on regenerative medicine in the areas of diabetes, liver and lung disease, neurologic disorders, and orthopedic surgery.”
The interdisciplinary collaboration that provides the foundation for the Center for Regenerative Medicine epitomizes Mayo Clinic’s approach to research and treatment. So, too, does a commitment to using talent and technology to enhance patient care.
“The Mayo history of being an unbelievable medical and scientific center is the reason I am here,” Dr. Terzic says. “We have extremely creative people here as well as the environment that allows them to develop definitive solutions to problems.”