The Heart of the Marrow - Silviu Itescu
by Vicki Brower
Posted February 15, 2002 · Issue 120
Abstract
Driven by the desire to help patients with failing hearts find better options, Silviu Itescu began investigating bone-marrow-related stem cells. In less than three years, this work laid the groundwork for what he hopes will be the first clinical trial with cardiac patients using autologous stem cells.
Silviu Itescu never had any intention of becoming a stem cell researcher, but he seems to have a knack for gravitating to areas of hot research. He received his training in rheumatology and immunology in his native Australia and at New York University. In the 1990s, Itescu applied his immunology background to infectious disease research when he discovered a connection between patients' human leukocyte antigen (HLA) status and their progression from HIV to AIDS. Then, in 1996, he was called upon to apply his expertise to transplantation medicine when New York-Presbyterian Hospital recruited him to establish a heart transplantation immunology department.
Stem cells were not on his mind. "My mission was to identify patients at high, mid, and low risk of rejection before transplant," says Itescu. While developing assays to determine individuals' rejection risks, monitoring post-transplantation patients, and developing new treatments to stave off and treat rejection, he learned enough about cardiology and transplantation medicine to begin looking for new solutions for severely ill cardiac patients. It was his experience with the limitations of heart transplantation that brought Itescu to stem cell research, looking for solutions to two ever-present problems: the risk of rejection and the chronic shortage of heart donors.
"For the past two and a half years, I've been learning about stem cells on the job," says Itescu, and he is rapidly becoming one of the leading adult stem cell scientists in the United States with research that may lead to a new stem cell therapy treatment of intractable heart disease. While he has been learning, Itescu has also been publishing research that is setting the stage for human clinical stem cell trials for heart repair. He hopes the trials will begin within a few months.
Itescu's patients are the sickest of the sick: individuals who have been ravaged by cardiovascular disease, which has left them in such a grave state that transplantation is the only means of extending their lives. His work with this population forced him to confront the fact early on that most of those who need transplants do not receive them due to a chronic shortage of donors: about 2,000 donors a year in the United States for about 60,000 patients who desperately need new hearts. Unfortunately, the donor pool has remained constant for the past decade. So, given a chronic shortage of hearts and the growing numbers of patients with cardiovascular disease, Itescu began looking for other treatments.
Itescu investigated two possible alternatives to heart transplantation: xenotransplantation and mechanical devices (the left ventricular assist device [LVAD] and the artificial heart). After studying xenotransplantation and after employing LVADs in critically ill patients, Itescu became disheartened by the immune barriers that each presented. While transgenic pigs are bred so that some of its organs' surface molecules are human rather than porcine to reduce acute rejection, Itescu believes that long-term rejection remains problematic and that it is likely to be insurmountable. "Mechanical devices offer different rejection problems. They provoke the body to mount a strong immune response," says Itescu. Ultimately, patients who get these devices often do poorly because their immune system goes into overdrive and eventually breaks down, leading to immune deficiency and frequent infections.
Itescu then began investigating bone marrow stem cells. Could bone marrow stem cells seed the damaged heart and stimulate the formation of new blood vessels and improve its function? If it is possible to lay down new blood vessels to deliver oxygen and other nutrients to damaged heart cells, it could cause cells to divide and repair oxygen-starved areas of the heart. In contrast to some other researchers in this field, Itescu firmly believes that to help a failing heart, it is necessary to produce robust blood vessels rather than implanting cells that are or become cardiomyocytes.
Last spring, Itescu published research showing that purified human bone marrow stem cells that express the c-Kit protein can be expanded with granulocyte stimulating factor (G-CSF) to produce cells with the functional characteristics of angioblasts (embryonic heart cells) [1 ]. When these angioblasts were reinfused into the bloodstream of rats with ischemic heart damage, they migrated directly to the heart - to the site of damage - where they arrested cell death and produced new blood vessels, resulting in functional improvement. "The new blood vessels enable new cardiomyocytes - heart muscle cells - to develop by providing a source of blood and other nutrients to the tissue," Itescu says. "By expanding and reinfusing these stem cells, we are trying to augment a naturally occurring process."
In research now in press, Itescu details which factors in the damaged heart signal that oxygen deprivation has occurred and attract stem cells to the damage to heal it, which factors push the angioblasts to differentiate properly, and which factors help create bigger blood vessels. On the basis of his research, Itescu believes that, eventually, it will be possible to treat acute heart attack patients by purifying and reinfusing their own bone marrow containing angioblasts within days of a heart attack. Using a patient's own cells will avoid any problem of tissue rejection. Speed of treatment is important after damage by ischemia and will be key in preventing further damage in the form of cardiac remodeling, which starts days after a heart attack and continues for months or years, further weakening the heart and leading to congestive heart failure and death.
As ambitious a clinician as he is about treating heart disease and its progressive debilitation in patients, Itescu is also cautious about doing the necessary basic research to ensure safety in humans. Moreover, he is also savvy enough to be alert to inherent conflicts of interest between researchers, their academic institutions, and biotech companies. "It can be a touchy situation, working through intellectual property issues and clinical trials, which require a lot of funding," he admits. Working with biotech companies may mean moving too rapidly, or too slowly, as business rather than science demands, he adds. Itescu is convinced that the work needs to take place at a university in partnership with a biotech company, but unlike many scientists who have evolved into businesspeople, Itescu is firm in his intention to remain in the lab and in the clinic.
In less than three years, Itescu's research with adult stem cells has laid the groundwork for what he hopes will be the first clinical trial with cardiac patients using autologous stem cells. Besides dedication, being single may be also a factor in moving his research forward so rapidly, Itescu admits. He has received strong support and encouragement from the medical school's new dean, Gerald Fischbach, a neurologist formerly at the National Institutes of Health , as well as the departments of medicine and surgery, which have also enabled the research to progress rapidly. For its part, the medical school is setting its sights on stem cell research and is currently building a good manufacturing practices (GMP) facility to process the cells.
Itescu hopes to begin the first protocol trial within the next few months in stable cardiac patients, following the review (and hopefully, approval) by New York-Presbyterian Hospital's institutional review board. "Phase I will most likely take place in 20 to 30 patients who have had heart attacks within a year or those with stable angina and an area of ischemia." Using perfusion scans, Itescu will track infused cells and improvements in blood flow and note any symptoms. He is confident that even the safety trial is likely to show some efficacy.
The next trial, a multicenter phase II trial, will most likely include patients who have had recent myocardial infarctions. It will examine cardiac function and mortality rates within the first six months, and from six months to a year, progression of heart disease and patients' use of regular cardiac medication - ACE inhibitors and beta-blockers. "If the phase II is successful, there may be no rationale to conduct a phase III in acute heart attack patients," Itescu said in his characteristically determined yet understated tone. Still to be determined: how many millions of cells will be reinfused into patients. Ultimately, Itescu hopes that the stem cell therapy he is developing will be used to treat chronic cardiac dysfunction, congestive heart failure, and occlusive coronary artery disease, which is the number one cause of mortality in the west.
Is it a coincidence that not once, but twice in a young career as an immunologist Itescu has found himself at the center of hot research - first AIDS, then stem cell research? "Probably not," he admits. And while Itescu regrets that his contact with patients has lessened of late while the research is on the front burner, he hopes to spend more time with patients in the future, as the work moves to the clinic.
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