Univ. of Washington and Sana researchers use gene editing to prep stem cells for heart repair
Human stem cell scientists have long dreamed of repairing damaged hearts, but have been stymied by research showing that the cells yield irregular heartbeats in laboratory animals. A new genetic engineering approach overcomes this barrier, according to a report at the annual meeting of the International Society for Stem Cell Research by scientists at the University of Washington and Sana Biotechnology, a Seattle-based company.
A heart attack typically kills about one billion cells, said Charles Murry, director of the Institute for Stem Cell and Regenerative Medicine at the UW, who presented the data Monday. Such massive cell death can lead to downstream effects such as heart failure, an often-debilitating condition that affects about 6.2 million people in the U.S. Using stem cells to repair the damage after a heart attack has long been a goal in his lab.
One major challenge in the field is that implanting cells into the hearts of laboratory animals can nudge the whole heart into beating rapidly, a condition called engraftment arrhythmia, said Murry, who is also a senior vice president and head of cardiometabolic cell therapy at Sana, which went public earlier this year.
“This engraftment arrhythmia, where the heart races too quickly, has been one of the major hurdles we’ve been trying to overcome en route to clinical trials,” said Murry in a press release.
In their study, Murry and his colleagues quelled engraftment arrhythmia using a genetic engineering strategy in cells implanted into pig hearts. Their next step is to see if the cells can repair heart damage in macaques — if those studies work, the researchers will initiate clinical trials in people, he said.
To quell the arrhythmia, Murry and his colleagues turned to CRISPR, the Nobel Prize-winning technique to knock out genes. They knocked out three genes in stem cells encoding different ion channels, molecules embedded in the cell membrane that mediate impulses that propagate heart beats. They also added DNA for another ion channel, KCNJ2, which mediates the movement of potassium across the membrane, “It’s a chill out channel,” Murry told GeekWire, “It tells the heart cell not to be so excitable.”
The engineered stem cells, derived from human embryonic stem cells, were nudged in a petri dish to produce heart muscle cells, which were then implanted into pigs via open heart surgery or a catheter. The result was an even heartbeat— the genetically altered cells did not cause engraftment arrhythmia.
The researchers landed on this strategy after years of effort, assessing which channels were present in the cells during arrhythmia, and knocking out multiple types of channels until they hit the right combination.
In their next set of experiments in macaques, “We want to make sure these cells are still effective,” said Murry, “They look good beating in culture, so I think they are going to be OK.” Moving forward, the researchers will also use induced human pluripotent stem cells, obtainable from adults and more amenable longer-term for clinical use.
In another recent study, published in Cell Systems, scientists at the Allen Institute for Cell Science took a close look at cardiac muscle cells derived from stem cells. They found that they could classify the state of the cells, such as how mature they were, by assessing both cell structure and which genes were turned on.
“This paints a broader picture of our cells. If someone wants to really understand and characterize a cell’s state, we found that having both of these types of information can be complementary,” said Kaytlyn Gerbin, Ph.D., a scientist at the Allen Institute for Cell Science in a statement. The findings provide a fine-tooth analysis of cell state, which may guide future experiments on cardiac muscle and other cell types.
Murry’s research was conducted primarily at the UW, with financial support from Sana. In addition to its cardiac program, Sana has cell and gene therapy programs in diabetes, blood disorders, immunotherapy and other areas.