Changing one gene could help people reduce dangerously high cholesterol levels 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 designed to show whether the experimental gene-editing therapy is safe to use in humans.
So it was, say the researchers. This was also effective: one infusion of the medicine knocked down low-density lipoprotein cholesterol (LDL) and triglycerides by about half—an effect that can reduce patients' risk of heart disease for the rest of their lives.
“Honestly, if you asked me 15 years ago if we could do this, I would have thought you were crazy,” said Dr. Steven Nissen, chief scientific officer of the Cleveland Clinic Heart, Vascular and Thoracic Institute and one of the study's investigators. “The results were quite impressive.”
The experimental drug uses CRISPRa gene editing tool that makes changes to an organism's genetic code. In this case, it manipulates one gene in the liver that typically increases cholesterol levels. Unlike cholesterol-lowering drugs such as statins, which must be taken daily, this approach should work consistently after one dose. (CRISPR Therapeutics makes the drug and helped fund the study.)
The study, which was also published Saturday in New England Journal of Medicinehas caused a mixture of excitement and concern among cardiologists.
“This is a good proof-of-principle study, which means we know we can do this,” said Dr. Carole Watson, co-director of the Preventive Cardiology Program at UCLA Health. “It doesn't answer the question: 'Should we do this?'”
The CRISPR technique can be thought of as altering a person's genetic structure throughout life. Therefore, its long-term safety is unknown. Ongoing studies will need to ensure that the therapy does not harm the liver, where its effects are primarily felt.
“Here’s the thing,” Watson said. “We already have really safe, really good LDL-lowering and triglyceride-lowering drugs that can be easily taken orally once a day. They're going to have to show us that CRISPR is very effective and safe. Long-term safety will be key.”
However, about half of people prescribed a statin daily stop taking them within a year, often due to side effects, according to Nissen. Moreover, the clinical trial included only patients who had unsuccessfully tried to lower their cholesterol using 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-term effects,” he said, “so we really need to make sure we understand the safety before we can provide these treatments.”
But if the drug is found to be safe, Shah said, “the future will be very promising because we will be able to care for patients at high risk for cardiovascular disease.”
Heart disease is the No. 1 cause of death among Americans. The 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 greater than 130 mg/dL. according to AGA. LDL levels below 100 mg/dl considered healthy for most adults.
The drug targets the ANGPTL3 gene, which tells the body to produce a protein that prevents the breakdown of cholesterol in the liver. Some people naturally have low-functioning versions of this gene, leading to lifelong reductions in LDL cholesterol and triglycerides, according to the study. The drug is designed to mimic this effect by turning off this gene so the liver can break down more cholesterol and fat.
The 15 study participants lived in Australia, New Zealand and the UK. They were between 50 and 60 years old. Thirteen were men. All had uncontrolled high LDL, triglycerides, or a combination of both.
At the start of the study, the average LDL cholesterol level was 155 mg/dL and the average triglyceride level was 192 mg/dL, well above what is considered healthy (below 150 mg/dL).
Participants received different doses of a drug called CTX310 in a single infusion lasting up to 4.5 hours. Some people have had side effects such as nausea or back pain during the infusion. One volunteer experienced a temporary spike in liver enzyme activity that eventually returned to normal. One person died of an unrelated cause several months after the infusion, the researchers said.
The highest dose was given to four participants. In these people, LDL cholesterol levels decreased by 48.9% and triglycerides decreased by 55.2% within two months of treatment.
“What's great about this ANGPTL3 target is that it not only lowers LDL, the bad cholesterol, but it also has some effectiveness in people with very high triglyceride levels,” said Dr. Elizabeth McNally, a human geneticist and cardiologist at Northwestern Feinberg School of Medicine in Chicago.
“It may be useful, but it remains to be seen how much better it is than existing treatments,” said McNally, who was not involved in the current study.
This is not the first time that an experimental gene therapy has proven effective in lowering cholesterol levels in early studies. Two studies presented at the 2023 AHA meeting. went for genes to lower cholesterol. Larger studies of these treatments are ongoing.
CRISPR technology is relatively new, and interest in the tool has been growing since it was first used in 2012. (Its inventors received the Nobel Prize in Medicine in 2020.) In 2023, the Food and Drug Administration approved the first CRISPR drug in the US. Kasgevy, which treats sickle cell anemia.
Nissen said the next phase of clinical trials for the CTX310 treatment will include more patients, including those in the United States. “We still have a ways to go, but this is the door to the future,” he said.
