The handful of patients suffered from serious heart disease that had caused chest pain and heart attacks. After trying the cholesterol-lowering medications available, they were unable to lower cholesterol as much as cardiologists recommended.
So they volunteered for an experimental gene-editing cholesterol-lowering treatment that was unlike anything previously tested 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 markedly reduce cholesterol levels in patients and appeared to be safe.
Only 10 patients participated in the trial, with an average age of 54 years. Each had a genetic abnormality, familial hypercholesterolemia, which affects about a million people in the United States. But the findings could also point the way for millions of other patients around the world facing heart disease, which remains a leading cause of death. In the United States alone, more than 800,000 people suffer heart attacks each year.
And although more trials will need to be conducted in a broader range of patients, gene editing experts and cardiologists said the treatment had the potential to transform preventive cardiology.
“Even for seasoned veterans in this field like me, this is a day we will remember,” said Fyodor D. Urnov, gene editor at the Innovative Genomics Institute in Berkeley, California. “I see today as a crossing of the Rubicon, in a good way. This is not a small step. It is a leap into new territory.”
Impressed with the data and the potential it shows, pharmaceutical giant Eli Lilly paid $60 million to collaborate with Verve Therapeutics and opted to acquire additional rights to Verve’s programs for an additional $250 million. If the edit continues to look promising, Eli Lilly hopes to help with larger studies.
“Until now, we thought of gene editing as a treatment that we should reserve for very rare diseases where no other treatment exists,” said Dr. Daniel Skovronsky, chief scientific and medical officer at Eli Lilly. “But if we can make gene editing safe and widely available, why not attack a more common disease?”
The new study was led by Dr. Sekar Kathiresan, CEO of Verve. The patients received a single infusion of microscopic lipid nanoparticles containing within them a molecular factory to edit a single gene in the liver, the site of cholesterol synthesis. The PCSK9 gene raises levels of LDL cholesterol, the bad kind. The plan was to block it.
The small lipid spheres were transported through the blood directly to the liver. They entered the liver cells and opened, revealing two molecules. One tells the DNA to create a gene editing tool and the other is a guide to get the editing tool to the gene that needs editing.
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 of Preventive Cardiology, who was not involved in the study. study. rehearsal.
The gene editing tool acts like a pencil and eraser. The eraser erases one letter from the target gene and the pencil writes a new one, deactivating PCSK9.
The goal: a unique cholesterol-lowering treatment that results in lifelong protection against heart disease.
The patients received different doses. LDL levels in the three who received the highest doses were reduced by 39 to 55 percent, enough to reach their cholesterol goal.
In the small study, those who received the highest doses had flu-like symptoms for a few hours. Two patients had serious adverse events that the study’s independent data safety and monitoring board considered to be a result of their underlying serious heart disease. The board recommended the researchers not stop the study.
One of them suffered a fatal cardiac arrest five weeks after receiving the infusion. An autopsy showed 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 receiving the infusion, but he had not reported it. If the researchers had known, he would not have received the treatment.
In some ways, the treatment is the culmination of studies that began a decade ago when researchers discovered rare but healthy individuals with cholesterol levels that seemed incredibly low. The reason was that his PCSK9 gene was mutated and no longer working. As a result, these people were protected from heart disease.
That led to the development of antibodies to block the gene. Patients inject the antibodies once a week. Then came a twice-yearly injection of RNA that prevents PCSK9 from being produced.
It seemed possible that such treatments, as well as statins for those whose cholesterol is more easily controlled, could help solve the problem of heart disease.
But heart disease persists as a cause of death. Even after people are diagnosed with heart disease, less than 60 percent of all patients take a statin. Only a quarter take one of the most effective high-intensity statins, Dr. Gulati said.
“Patients take it initially and then forget about it or decide they don’t need it,” he explained. “That happens more than you think.”
Dr. Michelle O’Donoghue, a cardiologist at Brigham and Women’s Hospital, said that because patients often don’t take their pills or injections, “there is a lot of interest, through gene editing, in a one-and-done treatment.” . and a response for life.”
Family history was the inspiration for Dr. Kathiresan of Verve Therapeutics. His uncle and her grandmother died of a heart attack. Her father suffered a heart attack at age 54. And then, on September 12, 2012, her brother Senthil, 42, returned from a run dizzy and sweaty. He was having a heart attack. He died nine days later.
At that point, Dr. Kathiresan said, 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 application to young people at heart risk is something that remains in the future. But, Dr. Gulati said, early gene editing in younger patients with genetically high cholesterol levels could prevent hardening of the arteries.
“It could be amazing medicine,” he said.
All of this depends on the success and safety of gene editing and the duration of its effects. The first patient was treated just six months ago. But a previous study in monkeys lasted two and a half years and the results of gene editing persisted.
Dr. Urnov, who said he is at genetic risk for heart disease, is optimistic for himself and his 6-year-old daughter.
“I honestly can’t wait for this drug to be available for heart disease prevention,” he said. “I love the idea of using gene editing as a vaccine for the prevention of heart disease.”