The few patients had severe heart disease that had caused chest pain and heart attacks. After trying available cholesterol-lowering medications, they were unable to lower their cholesterol levels as recommended by cardiologists.
So they volunteered for an experimental cholesterol-lowering treatment using gene editing that was unlike anything previously tried in patients.
The result, reported Sunday by Boston-based Verve Therapeutics at a meeting of the American Heart Association, showed that the treatment appeared to significantly lower cholesterol levels in patients and appeared to be safe.
Only 10 patients with an average age of 54 years took part in the study. Each had a genetic abnormality, familial hypercholesterolemia, which affects about a million people in the United States. But the findings could also provide guidance for millions of other patients around the world suffering from heart disease, which remains a leading cause of death. In the United States alone, more than 800,000 people suffer a heart attack each year.
And while further studies need to be done with a broader range of patients, gene editing experts and cardiologists said the treatment has the potential to transform preventative cardiology.
“Even for seasoned veterans in the field like me, this is a day we will look back on,” said Fyodor D. Urnov, genes editor at the Innovative Genomics Institute in Berkeley, California. “For me, today means crossing a Rubicon. in the right sense. This is not a small step. It’s a leap into new territory.”
Impressed by the data and the potential it showed, pharmaceutical giant Eli Lilly paid $60 million to collaborate with Verve Therapeutics and decided to acquire additional rights to Verve’s programs for an additional $250 million. If the work continues to look promising, Eli Lilly expects to help with larger studies.
“Until now, we thought gene editing was a treatment we should reserve for very rare diseases for which there is no other treatment,” said Dr. Daniel Skovronsky, chief scientific and medical officer of Eli Lilly. “But if we can make gene editing safe and widely available, why not fight a more common disease?”
The new study was conducted by Dr. Sekar Kathiresan, CEO of Verve. The patients received a single infusion of microscopic lipid nanoparticles that contained within them a molecular factory for editing a single gene in the liver, the site of cholesterol synthesis. The PCSK9 gene increases LDL cholesterol levels, the bad kind. The plan was to block it.
The small lipid spheres were transported directly to the liver via the blood. They penetrated liver cells and opened, revealing two molecules. One instructs DNA to create a gene editing tool, and the other is instructions on how to get the editing tool to the gene that needs to be edited.
The treatment “is almost like science fiction,” said Dr. Martha Gulati, director of preventive cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles and president of the American Society for Preventive Cardiology, who was not involved in the treatment trial.
The gene editing tool works like a pencil and an eraser. The eraser erases one letter of the target gene and the pencil writes in a new one, turning off PCSK9.
The goal: a single cholesterol-lowering treatment that leads to lifelong protection against heart disease.
The patients received different doses. The three people who received the highest doses saw their LDL levels drop by 39 to 55 percent — enough to reach their cholesterol goal.
In the small study, those who received the higher doses experienced flu-like symptoms for a few hours. Two patients experienced serious adverse events that the study’s independent data safety and monitoring board considered to be secondary to their underlying serious heart disease. The board advised the researchers not to stop the study.
One suffered a fatal cardiac arrest five weeks after receiving the infusion. An autopsy revealed that several of his coronary arteries were blocked.
The other patient suffered a heart attack the day after the infusion. It turned out that he had had chest pain before the infusion but had not reported it. If investigators had known this, he would not have received the treatment.
In some ways, the treatment is a culmination of studies that began a decade ago, when researchers discovered rare but healthy individuals with seemingly incredibly low cholesterol levels. The reason was that her PCSK9 gene had mutated and no longer worked. This meant that these people were protected from heart disease.
This led to the development of antibodies that block the gene. Patients inject themselves with the antibodies once a week. Then came an RNA injection twice a year, which prevents the formation of PCSK9.
It seemed possible that these treatments, as well as statins for those whose cholesterol levels are more easily controlled, could help solve the heart disease problem.
But heart disease is still considered deadly. Even after being diagnosed with heart disease, fewer than 60 percent of patients take a statin. Only a quarter take one of the more potent, high-intensity statins, Dr. said. Gulati.
“Patients start by taking it and then forget about it or decide they don’t need it,” she explained. “It happens more often than you think.”
Dr. Michelle O’Donoghue, a cardiologist at Brigham and Women’s Hospital, said that because patients so often don’t take their pills or injections, “there is a lot of interest in a one-and-done treatment using gene editing.” lifelong answer.”
Family history was the inspiration for Dr. Kathiresan at Verve Therapeutics. His uncle and grandmother died of heart attacks. His father suffered a heart attack at the age of 54. And then on September 12, 2012, his 42-year-old brother Senthil returned from a run, dizzy and sweaty. He had a heart attack. He died nine days later.
At that moment, said Dr. Kathiresan, he vowed to find a way to prevent what had happened to his brother from happening to anyone else.
Of course, even if gene editing works, its use in young people with heart risk is still a long way off. But, according to Dr. Gulati, early gene editing could prevent hardening of the arteries in younger patients with genetically high cholesterol levels.
“It could be an incredible medicine,” she said.
All of this depends on the success and safety of gene editing and its lasting effect. The first patient was only treated six months ago. But a previous study in monkeys lasted two and a half years and the gene editing results persisted.
Dr. Urnov, who said he has a genetic risk for heart disease, is optimistic for himself and his 6-year-old daughter.
“I really can’t wait until this drug becomes available to prevent heart disease,” he said. “I love the idea of using gene editing as a vaccine to prevent heart disease.”