Changing a single gene may help people lower dangerously high levels of cholesterol and other blood fats, according to new research presented Saturday at the American Heart Association’s annual meeting in New Orleans.
The goal of the 15-person phase 1 clinical trial was to show whether the experimental gene-editing treatment was safe for use in humans.
It was, the researchers said. And it was effective, too: A single injection of the drug cut low-density lipoprotein (LDL) cholesterol and triglycerides by nearly half, an effect that could reduce patients’ risk of heart disease for the rest of their lives.
“Honestly, if you had asked me 15 years ago if we would be able to do this, I would have thought you were crazy,” said Dr. Steven Nissen, chief academic officer of the Cardiovascular and Thoracic Institute at the Cleveland Clinic and one of the study’s researchers. “The results were absolutely amazing.”
The experimental drug uses CRISPR, a gene-editing tool that makes cuts and changes in the body’s genetic code. In this case, it manipulates a single gene in the liver that normally boosts cholesterol levels. Unlike cholesterol-lowering drugs like statins that must be taken daily, this approach is intended to work permanently after a single dose. (CRISPR Therapeutics manufactures the drug and helped fund the study.)
The research, which was also published on Saturday in New England Journal of MedicineIt created a mixture of excitement and anxiety among cardiologists.
“It’s a good proof-of-principle study, which means we know we can do this,” said Dr. Carol Watson, co-director of the Preventive Heart Disease Program at UC Health. “It doesn’t answer the question: Should we do this?”
CRISPR can be thought of as a lifelong change in a person’s genetic makeup. As such, its long-term safety is unknown. Ongoing studies will need to confirm that the treatment does not cause damage to the liver, where its effects appear primarily.
“That’s what it is,” Watson said. “We already have really good, safe drugs that lower LDL and triglycerides, which are easy-to-use drugs that are taken orally once a day. They will have to show us that CRISPR is very effective and safe. Long-term safety will be key.”
However, according to Nissen, about half of people who take statins daily stop using them within a year, often because of side effects. Furthermore, the clinical trial included only patients who had tried, unsuccessfully, to lower their cholesterol through standard methods.
The technology is far from being used in everyday practice “for good reason,” said Dr. Nishant Shah, a preventive cardiologist at Duke University Medical Center in Durham, North Carolina.
“These are long-term effects, so we really need to make sure we understand the safety before we can offer these treatments,” he said.
But if the drug is deemed safe, Shah said, “the future is very promising for being able to care for patients at high risk for cardiovascular disease.”
Heart disease is the number one cause of death among Americans. Buildup of fats in the blood including LDL cholesterol and triglycerides can clog arteries and lead to heart attack and stroke.
About a quarter of U.S. adults, 25.5%, have dangerously high LDL levels of more than 130 mg/dL. According to AHA. LDL levels Less than 100 mg/dL It is considered healthy for most adults.
The drug targets a gene called ANGPTL3, a gene It tells the body to make a protein that prevents the liver from breaking down cholesterol. According to the study, some people naturally have low-functioning versions of this gene, which leads to lifelong low levels of harmful cholesterol and triglycerides. The drug aims to mimic this effect, by turning off the gene so the liver can break down more cholesterol and fat.
The 15 trial participants lived in Australia, New Zealand and the United Kingdom, and were in their 50s and 60s. There were thirteen men. They all had uncontrolled high levels of low-density lipoprotein (LDL), triglycerides, or a combination of the two.
At the start of the trial, the average LDL cholesterol level was 155 mg/dL, and the average triglyceride level was 192 mg/dL, which is well above what is considered healthy (less than 150 mg/dL).
Participants received different doses of the treatment, called CTX310, in a single dose that lasted up to 4 1/2 hours. A small number of people experienced side effects such as nausea or back pain during the infusion. One volunteer developed a temporary elevation in liver enzymes that eventually returned to normal. One person died of an unrelated cause months after the injection, the researchers said.
The highest dose was given to four participants. In these people, LDL cholesterol was reduced by 48.9%, and triglycerides were reduced by 55.2% within two months of treatment.
“The nice thing about the ANGPTL3 target is that it not only lowers bad LDL cholesterol, but it also has some effectiveness on people who have very high triglycerides,” said Dr. Elizabeth McNally, a human geneticist and cardiologist at Northwestern Feinberg School of Medicine in Chicago.
“This could be beneficial, but it remains to be seen how better this will be than current treatments,” said McNally, who was not involved in the current research.
This is not the first time experimental gene therapy has been shown to lower cholesterol in early studies. Two studies presented at the AHA meeting in 2023 looked at genes that work to lower blood cholesterol levels. Larger studies on these treatments are underway.
CRISPR is relatively new, with excitement for the tool building since it was first used in 2012. (Its inventors won the Nobel Prize in Medicine in 2020.) In 2023, the Food and Drug Administration approved the first CRISPR drug in the United States, CasGevi, which treats sickle cell disease.
The next phase of clinical trials for CTX310 will include more patients, including people in the United States, Nissen said. “We have a ways to go, but this is the door to the future,” he said.