Altering a single gene may help people lower dangerously high levels of cholesterol and other fats in the blood, according to new research presented Saturday at the annual meeting of the American Heart Association in New Orleans.
The Phase 1 clinical trial of 15 people was intended to show whether the experimental gene-editing therapy was safe to use in humans.
It was, the researchers said. It was also effective: One infusion of the medicine drove down low-density lipoprotein (LDL) cholesterol and triglycerides by about half — an effect that could decrease patients’ heart disease risk for the rest of their lives.
“Frankly, if you’d 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 at the Cleveland Clinic’s Heart, Vascular & Thoracic Institute and one of the study’s investigators. “The results were pretty spectacular.”
The experimental drug employs CRISPR, a gene-editing tool that makes cuts and changes to 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 need to be taken daily, this approach is meant to work permanently after one dose. (CRISPR Therapeutics makes the drug and helped fund the study.)
The research, which was also published Saturday in The New England Journal of Medicine, created a mix of excitement and concern among cardiologists.
“It’s a good proof-of-principle study, meaning we know we can do it,” said Dr. Karol Watson, co-director of the Program of Preventive Cardiology at UCLA Health. “It doesn’t answer the question, ‘Should we do it?’”
The CRISPR technique would be considered a lifelong change in a person’s genetic makeup. As such, its long-term safety is unknown. Ongoing studies will need to make certain that the therapy doesn’t cause harm to the liver, where its effects are primarily seen.
“Here’s the thing,” Watson said. “We already have really safe, really good medications that lower LDL and triglycerides that are easy, once-daily oral medications. They will have to show us that CRISPR is very effective and safe. Long-term safety will be key.”
According to Nissen, however, about half of people prescribed daily statins stop using them within a year, often because they have side effects. Moreover, the clinical trial only included patients who had tried, without success, to lower their cholesterol through standard approaches.
Dr. Nishant Shah, a preventive cardiologist at Duke University Medical Center in Durham, North Carolina, said the technology is far from being used in everyday practice “for good reason.”
“These are long-lasting effects,” he said, “so we really need to make sure we understand safety before we can provide these therapies.”
But if the drug is deemed to be safe, Shah said, “the future is very promising to be able to take care of patients at high risk for cardiovascular disease.”
Heart disease is the No. 1 cause of death for Americans. The accumulation 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 the AHA. LDL levels below 100 mg/dL are considered healthy for most adults.
The drug targets a gene called ANGPTL3, which tells the body to make a protein that prevents the liver from breaking down cholesterol. Some people have naturally low-functioning versions of this gene, resulting in lifelong reductions in LDL cholesterol and triglyceride levels, according to the study. The drug is meant to mimic this effect, by turning off the gene so the liver is able to break down more cholesterol and fats.
The 15 trial participants lived in Australia, New Zealand and the U.K. They were in their 50s and 60s. Thirteen were men. All had uncontrolled high LDL, triglycerides or a combination of the two.
At the beginning of the trial, the median LDL cholesterol level was 155 mg/dL, and the median triglyceride level was 192 mg/dL, far above what’s considered healthy (below 150 mg/dL).
Participants got different doses of the treatment, called CTX310, in a single infusion that lasted up to 4 ½ hours. A few people had side effects like nausea or back pain during the infusion. One volunteer had a temporary spike in liver enzymes that eventually returned to normal. And one person died for an unrelated reason months after the infusion, researchers said.
The highest dose was given to four participants. In those people, LDL cholesterol decreased by 48.9%, and triglycerides fell by 55.2% within two months of treatment.
“What’s nice about this target of ANGPTL3 is that it not only lowers the LDL, the bad cholesterol, but it also has some effectiveness on people who have very high triglycerides,” said Dr. Elizabeth McNally, a human geneticist and cardiologist at the Northwestern Feinberg School of Medicine in Chicago.
“This could be helpful, but it really does remain to be seen how this is better than existing therapies,” said McNally, who was not involved with the current research.
This isn’t the first time an experimental gene therapy has proved successful at driving down cholesterol in early studies. Two studies presented at the AHA meeting in 2023 went after genes to lower cholesterol levels. Larger studies on those treatments are ongoing.
CRISPR technology is relatively new, with excitement growing for the tool 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 U.S., Casgevy, which treats sickle cell disease.
Nissen said the next phase of clinical trials on the CTX310 treatment will include more patients, including people in the U.S. “We’ve got a ways to go, but this is the door to the future,” he said.
Kaan Ozcan contributed.