The first-of-its-kind study in heart attack patients will seek to demonstrate the safety, and roughly measure efficacy, of three intravenous doses of adult human stem cells versus placebo in lessening damage to heart muscle within ten days of first heart attack. The treatment recently passed an early safety test and has been approved for study in more patients at higher doses. That process will get underway shortly in Rochester.
"The potential to re-build damaged heart muscle by implanting stem cells that then become new muscle cells is one of the most exciting in cardiology," said Craig R. Narins, M.D., assistant professor of Cardiology at the medical center and principal investigator for the current study. "This study will seek to ensure that stem cell therapy is safe in treating heart failure, a major cause of death in heart attack survivors."
Heart Injury Overwhelms Regeneration
A human embryo starts with one cell that divides to become many. Early on, stem cells change, or differentiate, from non-specific precursors into specialized cells that make up organs. Within a layer of the embryo called the mesenchyma, for example, mesenchymal stem cells (MSCs) can go on to become either cartilage, bone or muscle cells, depending which genetic signals they receive. Some MSCs persist beyond the fetal stage into adulthood in the bone marrow, where researchers believe they await the call to differentiate and replace damaged tissue.
In the process of regeneration, humans continually replace old blood and skin cells with new ones by re-starting some of the mechanisms (e.g. stem cell differentiation) that allowed those tissues to first develop in the fetus. Other tissues, like heart muscle, have almost no ability to regenerate. When humans receive an injury too serious to repair through regeneration, a process called fibrosis kicks in to patch the wound, but also leaves scar tissue that reduces the organ's performance.
More than half a million Americans each year have their first heart attack, a sudden blockage of an artery that deprives heart muscle of blood and oxygen. The resulting injury and scarring often contribute to a gradual loss of the heart's pumping strength, a condition known as congestive heart failure.
Researchers hope that cellular cardiomyoplasty, the use of transplanted stem cells to replace lost heart muscle cells, will do what current treatments cannot: prevent heart muscle loss after heart attack. Animal studies have shown that MSCs injected into heart muscle following a heart attack decreased the death of muscle cells and increased pumping strength.
The new study is a randomized, double-blind, placebo-controlled, Phase I clinical trial with patients randomized to receive either an injection of 0.5 million, 1.6 million or 5.0 million cultured adult mesenchymal stem cells (tradename: Provacelä) per kilogram of body weight, or placebo. There will be 17 active study sites.
Along with the treatment or placebo, all patients will receive standard treatment, including techniques to maximize blood flow to damaged areas, pain relief, oxygen, anti-coagulants, beta-blockers, nitrates, ace-inhibitors and advice on reducing risk factors.
Forty-eight patients will participate in the trial, 22 of which have already been enrolled. Male and female patients are eligible and must be between the ages of 21 and 85 and in good overall health, with the exception of a recent heart attack. Trial entry must occur within 10 days of first heart attack, and patients will be followed for two years afterward.
The trial, to be conducted according to U.S. Food and Drug Administration guidelines, is designed to evaluate safety of treatment with stem cells obtained from healthy, unrelated, adult donors (not from a fetus, embryo or animal). Provacel, developed by Osiris Therapeutics, Inc., is not yet an approved or marketed therapy.
Blood Bank Model
Experts believe that mesenchymal stem cells for many reasons have tremendous potential to become the basis for a powerful new treatment area in cardiology. For instance, research has shown that MSCs, like Blood Type O, are universally compatible, meaning they can be transplanted from person to person without fear of rejection by the recipient's immune system.
Other approaches - like harvesting stem cells from the patients' own tissue - can be expensive, time-consuming and limited in the numbers of cells produced. Stem cells donated by other humans (allogeneic) make possible the storage of stem cell supplies ready for immediate use as heart attack patients arrive at hospitals.
From a small sample of bone marrow, researchers can grow billions of allogeneic stem cells in cultures, controlled environments that mimic human tissue. Cultured MSCs (hMSCs) are used already in the treatment of some cancers.
In addition, while initial studies injected cells directly into the heart, the picture emerging is that MSCs can be delivered to the heart by a standard injection in the arm. MSCs actually home in on the tissue damaged by heart attack, according to researchers. It has been shown that higher animals store MSCs in the bone marrow, and release them into the blood stream after injury, where they can rush to the site of damage to aid in wound repair the same way that white blood cells rush in to fight infection.
Also like white blood cells, MSCs home for only a short time following injury, so treatment needs to begin as soon as possible after heart attack.
"This technology makes it possible to mass produce stem cells and transplant them from person to person," Narins said. "All of this may make it possible to bank stem cells ahead of time for later, emergency use the way we store blood in blood banks."
Major challenges remain in making cardiomyoplasty a reality, several of which will be addressed by the current trial. For example, implanted stem cells have been shown in some studies to only partly differentiate, with the end result lacking some of the characteristics of a mature heart muscle cell. While studies show that partially differentiated stem cells still prevent muscle cell loss when implanted, researchers seek ways to push differentiation further.
In addition, early studies also found that most implanted MSCs either re-enter the circulation or die rather than engraft to the heart muscle wall to form new muscle cells. In response, researchers are pursuing gene therapy -- the insertion of desired genes into a cell - to increase the number of stem cells that live on as new muscle cells and to drive differentiation.
"We are proud to partner with leading research institutions to bring this exciting new therapy into the clinical setting," said C. Randal Mills, Ph.D., president and CEO of Osiris Therapeutics, Inc.
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