A gene therapy to restore damaged tissue after a heart attack clears pigs
James Martin had been trying to manipulate a particular gene to regrow heart and bone cells for six years when, while brainstorming for a grant one day in 2009, he stumbled on an old fruit fly study out of Albert Einstein Medical Center in New York.
The study showed that mutations in a pathway called Hippo (so named because it can lead to a hippopotamus-like growth) could cause fly tissues to grow at abnormal rates. Martin, a professor at Baylor College of Medicine, wondered whether it may do the same in heart cells.
Soon enough, the results were so dramatic that he shifted his focus. He showed he could get mice to completely recover after a devastating heart attack. “Our findings indicate that the failing heart has a previously unrecognized reparative capacity,” he wrote after a 2017 study.
And on Thursday, Martin unveiled an approach that could soon have implications in humans. Martin and his team devised a gene therapy that successfully regrew the heart cells of pigs who have been manipulated to resemble patients recovering from a heart attack. The results were published in Science Translational Medicine.
“We were over the moon,” Martin told Endpoints News. “We were taking this from the beginning of a very basic science question to something that could be really transformative as a heart failure therapy.”
Martin is now working with the FDA and a startup he founded, Yap Therapeutics, to move the therapy into the clinic. Outside experts praised the results, while cautioning that significant obstacles remain.
Ron Crystal, a professor of gene therapy at Cornell, noted the pigs saw a 14.3% increase in heart function, as measured by ejection fraction, i.e. the amount of blood that leaves the heart every time it contracts. That’s far from a cure, but it would represent the only therapy that can actually restore function after a heart attack. Current therapies simply try to limit the damage.
“It’s a very nice example taking basic biology and translating that to a possible therapy for humans,” Crystal told Endpoints. “If you can restore 12% to 15%, that’s great.”
After a heart attack, millions of cells in the heart die, generally leaving the remaining muscle unable to shoulder the burden of pumping blood to the whole body. About half of all heart failure patients die within five years.
Clinical trials for drugs to slow progress on that front have been a wasteland, with drugs from Merck, Amgen and Novartis all failing to show significant improvements in survival, even if they reduce hospitalizations. A variety of approaches have been put forth to regenerate the heart, including cell and gene therapy, but they have largely fizzled after safety issues arose in animals or early trials produced few results.
In Martin’s study, his team used an old technology called short hairpin RNA, designed to knock out the Hippo pathway. They packaged those into an AAV vector and delivered it via a catheter into the cells that surrounded the site of the heart attack, a ground zero of dead muscle cells.
The Hippo pathway acts as a master regulator across the animal kingdom, allowing growth in early development and stopping it as organisms mature. The hairpin would reduce the pathway’s function, allowing the cells to divide again.
“You’re turning back the clock,” said Crystal.
Martin saw the heart cells proliferate for about three months. The fact that the cells stopped was important: A previous effort by another lab to regenerate heart cells worked too well. The cells just kept dividing, like a cancer.
To translate into the clinic, Martin will have to show longer term safety data, proving only right heart cells grow and then stop growing at the right time. He also plans to tinker with other genes in hopes of restoring heart function by more than just 15%.
“It’s still preliminary,” Martin said. But “we have overcome many of the obstacles”