Medical researchers have restored the function of damaged hearts in macaque monkeys, using heart muscle cells derived from human embryonic stem cells. Now they want to do the same for humans.
The technique, detailed today in the journal Nature Biotechnology, could go into human clinical trials as early as 2020, said senior study author Charles Murry, director of the Institute for Stem Cell and Regenerative Medicine at the University of Washington School of Medicine.
“I’ve been in research since 1984, and this worked better than anything I’ve ever seen for the treatment of heart failure,” he told GeekWire.
That’s a big deal, because heart failure is a leading cause of death around the world. In this context, we’re not talking about the heart stopping suddenly. We’re talking about cardiovascular damage that takes its toll on the ability of the heart to pump blood.
About 6.5 million Americans are living with heart failure. Victims typically become weaker, more fatigued and more short of breath over time. Half of those who develop the condition die within five years.
“All of the treatments treat the symptoms, and not the root cause,” Murry said.
Treating the root cause would involve building up new heart muscle to replace the damaged cells. The development of techniques to isolate and grow human embryonic stem cells, 20 years ago, spurred Murry and his colleagues to work on just such a muscle-building strategy.
Embryonic stem cells have the ability to transform themselves into almost any type of cell in the body, raising the promise of new regenerative therapies. But coaxing the cells to do what’s desired has been devilishly difficult.
“For 15 years, I told everybody that this was five years away from the clinic,” Murry said. “I had no idea when I started this what I was doing.”
The team experimented with mice, then with rats, then with guinea pigs — and most recently with macaque monkeys, which are considered among the closest animal models for human physiology.
For the newly reported experiment, researchers induced heart attacks in nine monkeys, and then measured the resulting reduction in cardiac function.
The standard measurement checks how much of the blood is pumped out of the heart’s left ventricle with each beat. That’s known as the ejection fraction. The monkeys who suffered the attacks had their ejection fraction reduced from about 65 percent to 40 percent — which qualifies as heart failure.
The key step in the experiment involved taking advantage of human embryonic stem cells to create billions of heart muscle cells, or cardiomyocytes. Two weeks after their heart attacks, some of the monkeys received injections of those muscle cells in the regions of the heart around their scar tissue. Other monkeys were given only cell-free injections.
The monkeys were treated with drugs to ensure that their immune systems wouldn’t fight off the injected human cells.
Four weeks after treatment, the condition of the monkeys who didn’t get the human cells was unchanged. But the monkeys who were given the cells improved their ejection fraction to almost 50 percent. What’s more, researchers saw evidence that the new cells had indeed taken root within the heart’s scar tissue.
Two of the treated monkeys, plus one of the untreated monkeys, were followed for another two months to see how the recovery progressed. At the end of the three-month period, the untreated monkey was slightly worse off, while the two treated monkeys registered ejection fractions of 61 and 66 percent. Those are essentially normal levels.
Murry said the experiment addressed longstanding questions about whether cells derived from human embryonic stem cells can help hearts recover. “The answer is a resounding yes,” he said.
He estimated that it’ll take another two years or so to lay the groundwork for human clinical trials, most likely beginning in the Seattle area.
One issue has to do with how a person’s immune system would respond to the injected cells. Gene-edited cells could reduce those concerns, but Murry doesn’t think it’d be necessary to custom-design identically matched cells for heart patients. Going that route would be prohibitively expensive, he said.
Instead, Murry envisions a cell bank with frozen “off-the-shelf” cells that could go into any patient with only moderate immune suppression.
“Our approach is to make it like O-negative blood,” Murry said. He noted that a Seattle-based venture known as Universal Cells, which was recently acquired by Astellas, is already working on a similar strategy for creating gene-edited universal donor cells.
The therapy would probably work best two to four weeks after a heart attack, when the scar tissue is still fresh, Murry said.
“Things are really heating up” in cell therapy, and not just for treating heart disease, Murry said. Cells derived from human embryonic stem cells are being used experimentally to treat macular degeneration and spinal cord injury as well as heart disease. Parkinson’s Disease and diabetes may not be far behind.
“All these things are in the pipeline,” Murry said.
Lead authors of the Nature Biotechnology paper, titled “Human Embryonic Stem Cell-Derived Cardiomyocytes Restore Function in Infarcted Hearts of Non-Human Primates,” are Yen-Wen Liu, Billy Chen and Xiulan Yang. The paper has 27 authors in all. Three of the authors — Murry, W. Robb MacLellan and R. Scott Thies — report that they’re scientific founders and equity holders in Cytocardia, a commercial venture that may qualify as a competing interest.
The experiments were funded by grants from the National Heart, Lung and Blood Institute; the Washington Research Foundation, UW Medicine and community philanthropists.