The handful of patients suffered from serious heart disease that caused chest pain and heart attacks. After trying available cholesterol-lowering medications, they were unable to get cholesterol levels as low as cardiologists recommended.
So they volunteered for an experimental cholesterol-lowering treatment using gene editing that was unlike anything that had been tried before 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 reduce cholesterol levels in patients and appeared safe.
The trial included only 10 patients, 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 these findings could also pave the way for millions of other patients around the world who suffer 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 although more trials in a wider range of patients will need to be conducted, gene editing experts and cardiologists said the treatment has the potential to transform preventative cardiology.
“Even for seasoned veterans of this field like me, this is a day we will look back on,” said Fyodor D. Urnov, a gene editor at the Innovative Genomics Institute in Berkeley, California. “I view today as crossing a Rubicon, in a good way. It’s not a small step. It’s a leap into new territory.
Impressed by 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 edition continues to show promise, Eli Lilly hopes to contribute to larger studies.
“Until now, we viewed gene editing as a treatment that we should reserve for very rare diseases for which there are no other treatments,” said Dr. Daniel Skovronsky, Eli Lilly’s chief scientific and medical officer. “But if we can make gene editing safe and widely available, why not tackle a more common disease?”
The new study was led by Dr. Sekar Kathiresan, CEO of Verve. Patients received a single infusion of microscopic lipid nanoparticles containing a molecular factory to modify a single gene in the liver, the site of cholesterol synthesis. The PCSK9 gene increases levels of LDL cholesterol, the bad cholesterol. The plan was to block him.
The small lipid spheres were transported by the blood directly to the liver. They entered liver cells and opened, revealing two molecules. One instructs DNA to create a gene editing tool, and the other is a guide to getting the editing tool to the gene that needs to be edited.
The treatment “almost sounds 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, which did not participate in the study. trial.
The gene editing tool acts like a pencil and eraser. The eraser erases one letter of the target gene and the pencil writes a new one, deactivating PCSK9.
The goal: a unique treatment to lower cholesterol that protects against heart disease for life.
The patients received different doses. LDL levels in the three people given the highest doses fell by 39 to 55 percent – enough to get them to their cholesterol goal.
In the small study, those who received the highest 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 the result of their underlying serious heart disease. The board advised researchers not to discontinue the study.
One of them had a fatal cardiac arrest five weeks after receiving the infusion. The autopsy showed that several of his coronary arteries were blocked.
The other patient had a heart attack the day after the infusion. It turned out that he had experienced chest pain before receiving the infusion, but had not reported it. If investigators 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 whose cholesterol levels appeared incredibly low. The reason was that their PCSK9 gene had been mutated and no longer worked. As a result, these people were protected from heart diseases.
This led to the development of antibodies to block the gene. Patients inject the antibodies once a week. Then came a twice-yearly RNA injection that prevents PCSK9 production.
It seemed possible that these treatments, along with statins for those whose cholesterol levels are more easily controlled, could help solve the problem of heart disease.
But heart disease remains deadly. Even after a diagnosis of heart disease, fewer than 60 percent of all patients take a statin. Only a quarter of them take one of the more effective high-intensity statins, Dr. Gulati said.
“Patients take it at first, then they forget or decide they don’t need it,” she said. “It 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’s a lot of interest, through gene editing, in treatment unique and finished. and a lifetime response.
Family history was the inspiration for Dr. Kathiresan of Verve Therapeutics. His uncle and grandmother died of heart attacks. His father had 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 sweating. He was having a heart attack. He died nine days later.
At that moment, 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 risk of heart disease is not yet far away. But, Dr. Gulati said, early genetic modification in younger patients with genetically high cholesterol levels could prevent hardening of the arteries.
“This could be an incredible medicine,” she said.
This all depends on the success and safety of the genetic modification and how long its effects last. 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 says he has a genetic risk for heart disease, is optimistic for himself and his 6-year-old daughter.
“I honestly can’t wait until this drug becomes available for the prevention of heart disease,” he said. “I love the idea of using gene editing as a vaccine for heart disease prevention.”