Scientists Find a Way to Cut Cholesterol With a Single Gene Edit

For decades, people with dangerously high cholesterol have faced a familiar reality: lifelong medication, regular injections, and a constant effort to keep a major risk factor for heart disease under control. Now, scientists are testing a radically different approach that could eventually change that routine.

A one-time gene-editing treatment lowered LDL cholesterol by roughly 50% in a small group of patients, with the effect lasting for more than a year. The findings are still early, but they have raised a remarkable possibility: could doctors one day treat severe cholesterol problems by changing a single gene?

A One-Time Treatment With Lasting Results

The experimental treatment uses CRISPR-Cas9, a gene-editing technology often described as a biological tool capable of cutting genetic material at a targeted location. Researchers used it to alter a gene connected to the body’s regulation of cholesterol and triglycerides.

The initial pilot study involved 15 people with dangerously high cholesterol that had not responded adequately to existing medications. The researchers tested five different doses of the treatment, with the strongest results appearing among the four participants who received the highest dose.

At two months after treatment, those participants had an average 55% reduction in triglycerides and nearly a 50% reduction in LDL cholesterol. More than a year later, the results had largely held, with triglycerides nearly 48% lower and LDL cholesterol reduced by almost 53%.

The durability of the treatment was one of the biggest questions facing researchers. Dr. Luke Laffin, the study’s lead author and a preventive cardiologist at Cleveland Clinic, said the new data provided an early answer.

“Is something like this truly a one and done? That was always the question,” Laffin said. He added that the reductions in LDL cholesterol and triglycerides seen shortly after treatment had lasted for more than a year.

The findings do not prove that the treatment will work permanently. The study was extremely small, and participants will need to be monitored for much longer. Still, the fact that the effect persisted for a year has given researchers reason to continue testing the approach.

Scientists Took Inspiration From a Rare Genetic Mutation

The treatment focuses on a gene called ANGPTL3, which plays a role in regulating LDL cholesterol and triglycerides. The idea did not begin with a laboratory invention. It began with people who naturally carry an unusual genetic mutation.

According to the researchers, around 1 in 250 people in the United States may have one or both copies of the ANGPTL3 gene naturally switched off. Those individuals can have exceptionally low levels of LDL cholesterol and triglycerides throughout their lives without apparent negative consequences linked to the mutation.

The mutation also appears to offer substantial protection against cardiovascular disease. That observation gave scientists an intriguing idea: if nature had already demonstrated that reducing ANGPTL3 activity could be protective, perhaps medicine could reproduce part of that effect.

Dr. Steven Nissen, the study’s senior author and chief academic officer of Cleveland Clinic’s Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute, described the naturally occurring mutation as a source of inspiration for the experimental therapy.

“It’s a naturally occurring mutation that’s protective against cardiovascular disease,” Nissen said. “And now that CRISPR is here, we have the ability to change other people’s genes so they too can have this protection.”

The concept represents a major shift from traditional treatment. Most cholesterol medications work by changing biological processes temporarily, which means patients must continue taking them. Gene editing aims to make a lasting change inside targeted cells.

Why Researchers Are Targeting the Liver

Scientists are not attempting to edit genes throughout the entire body. The experimental treatment is designed to focus on the liver, an organ deeply involved in producing and regulating cholesterol and triglycerides.

The one-time infusion carries gene-editing technology intended to reach liver cells. Once there, the treatment is designed to reduce the activity of ANGPTL3 and create a lasting effect on the body’s management of blood fats.

This targeted approach differs from the naturally occurring mutation that inspired the treatment. A person born with an inactive ANGPTL3 gene carries that change throughout the body, while the experimental therapy concentrates on the liver.

Nissen said that focus could be reassuring from a safety perspective because it reduces the likelihood of editing genes in other parts of the body. However, long-term research will still be needed to understand the full consequences of the treatment.

The study also reflects a broader direction in cardiovascular research. Scientists have spent years identifying genes that influence cholesterol levels, then developing drugs to interfere with the proteins those genes produce.

Another major target has been PCSK9, a gene involved in regulating LDL cholesterol. Existing drugs can block the PCSK9 pathway, while experimental gene-editing approaches aim to suppress its activity more permanently.

ANGPTL3 and PCSK9 are different targets, but the research is driven by a similar ambition. Scientists want to determine whether changing a genetic pathway can provide long-lasting protection against a major contributor to heart disease.

The Highest Dose Produced the Biggest Drop

The pilot study was designed to test both safety and different treatment doses. Participants received doses ranging from 0.1 milligrams per kilogram to 0.8 milligrams per kilogram.

The highest dose produced the most dramatic reductions in LDL cholesterol and triglycerides. However, only four people received that dose, which means researchers cannot yet predict how consistently the treatment would work in a much larger population.

The initial study also recorded several medical events that require careful examination. Most reported side effects were minimal, including irritation at infusion sites. One participant experienced a spinal disk herniation, while another developed elevated liver enzymes.

The liver enzyme levels returned to normal within two weeks, according to the researchers. One participant also died six months after receiving the infusion, although Nissen said the death was not believed to be connected to the treatment.

The participant who died had extensive and advanced cardiovascular disease and had received the smallest dose tested. Nissen said that dose did not produce a meaningful treatment effect.

The early results are therefore encouraging, but they cannot settle questions about long-term safety. The U.S. Food and Drug Administration has recommended that people participating in gene-editing trials be followed for 15 years after trials are completed to monitor for possible long-term adverse effects.

Researchers also observed a roughly 20% reduction in HDL cholesterol at both two months and one year. HDL is commonly known as “good cholesterol,” and scientists will need more data to understand what that reduction could mean over time.

Existing Drugs Already Lower Cholesterol Effectively

The excitement surrounding gene editing should not create the impression that current cholesterol treatments are ineffective. Several existing medications can already reduce LDL cholesterol to levels similar to those seen in the experimental study.

Statins remain among the most commonly used cholesterol-lowering medications. Other treatments include injectable drugs that affect biological pathways involved in LDL regulation, including PCSK9 inhibitors that can produce major reductions in LDL cholesterol.

Research cited in the reference material also describes inclisiran, a treatment that uses RNA interference to reduce the production of PCSK9. Unlike traditional PCSK9 inhibitors, which block the protein after it is produced, inclisiran works by reducing its production.

The major attraction of gene editing is therefore not necessarily that it can lower cholesterol more than every existing drug. The attraction is the possibility that the effect could last for years after a single treatment.

For some patients, that distinction could be enormous. A person diagnosed with severe inherited high cholesterol at a young age may otherwise face decades of daily medication or repeated injections.

Dr. Ann Marie Navar, a preventive cardiologist at UT Southwestern Medical Center who was not involved in the ANGPTL3 study, previously explained why the prospect could be particularly significant for younger patients.

“If you’re 20 and you have really high cholesterol, it may make a lot more sense to have a one-time treatment that doesn’t require you to have to take a pill every single day or shot every two weeks for the next 60 years,” Navar said. “The potential for this is just enormous.”

Long-Term Treatment Can Be Difficult to Maintain

Modern medicine already has multiple ways to reduce cholesterol, but keeping people on treatment remains a major challenge. Some patients experience side effects, while others face difficulties involving cost, insurance, access, or the demands of maintaining a daily routine.

Researchers estimate that only about half of people take their cholesterol medications more than 80% of the time. Between 33% and 50% of people may stop taking statins within a year after beginning treatment.

Those numbers help explain why a one-time treatment has generated so much interest. A therapy that does not require constant medication could potentially remove some of the barriers that make long-term cholesterol management difficult.

However, permanence also creates a major difference between gene editing and traditional medicine. A pill can be stopped, and an injection schedule can be changed. A successful genetic alteration may be far more difficult to reverse.

Scientists will therefore need to answer several major questions before a treatment like this could become widely available:

• How long will the cholesterol reductions actually last?
• Can the treatment remain safe in hundreds or thousands of patients?
• Will lower cholesterol levels translate into fewer heart attacks?
• What are the long-term consequences of changing ANGPTL3 activity?
• Which patients would benefit enough to justify a permanent intervention?

Those questions will determine whether the treatment eventually becomes a specialized option for people with severe disease or something that could be considered more broadly.

Why Scientists Want to Lower LDL Cholesterol

LDL cholesterol is commonly called “bad cholesterol” because high levels can contribute to the buildup of fatty plaque inside arteries. Over time, that buildup can restrict blood flow and increase the risk of heart attacks and other cardiovascular problems.

A typical LDL level is around 100, according to the reference material. People with existing heart disease or severe inherited cholesterol disorders may be encouraged to lower their levels much further.

For many people, diet, exercise, and medication can significantly improve cholesterol levels. However, some inherited conditions make LDL cholesterol extremely difficult to control through lifestyle changes alone.

Familial hypercholesterolemia is one such condition. It can cause very high LDL levels and is associated with an increased risk of premature heart attacks.

Scientists have long been fascinated by naturally occurring genetic variants because they provide clues about what happens when the body’s cholesterol-regulating systems function differently. Some variants increase cardiovascular risk, while others appear to offer powerful protection.

The discovery of people with naturally low cholesterol due to genetic changes helped inspire several modern treatments. Gene editing takes the concept further by asking whether scientists can intentionally reproduce some of those protective effects after a person is born.

Nissen said the rapid development of this technology would have seemed extraordinary not long ago. “If you’d asked me 15 years ago if we could have done something like this, I would have thought you were crazy,” he said.

A Larger Trial Is Already Underway

The next stage of research is now underway in the United States and Australia. The new clinical trial is expected to include up to 40 people receiving the highest dose of the treatment.

That study should give researchers more information about safety, durability, and the consistency of the cholesterol reductions. Even a successful trial would still represent only another step in a much longer development process.

The treatment would need to progress through larger phase 2 and phase 3 clinical trials before regulators could consider approving it for broader use. That process can take years, particularly when researchers are dealing with a technology designed to make lasting genetic changes.

Interest from potential patients has already been strong. Laffin said researchers were surprised by the number of people who contacted medical organizations and Cleveland Clinic after hearing about the trial.

“We didn’t know patients would be willing to undergo genetic treatment, but clearly, they are,” Laffin said. The response reflects how difficult severe cholesterol disorders can be to manage over a lifetime.

For people who face decades of medication while carrying a persistent risk of heart disease, the possibility of a single treatment is difficult to ignore. Scientists now need much larger studies to determine whether that possibility can become a safe medical reality.

Gene Editing Could Change Heart Treatment

The ANGPTL3 study is part of a larger effort to use gene editing against cardiovascular disease. Researchers are investigating genetic approaches for several inherited heart conditions that currently have limited treatment options.

Some of the most closely watched work involves PCSK9, where scientists are exploring ways to permanently reduce the production of a protein linked to higher LDL cholesterol. Other research is examining genetic therapies for conditions such as cardiac amyloidosis and hypertrophic cardiomyopathy.

The long-term goal is ambitious. Instead of repeatedly treating the consequences of a biological problem, scientists want to determine whether they can alter the pathway responsible for the problem in the first place.

That approach could eventually transform treatment for some inherited diseases, but the risks must be understood with equal care. Early results from a small group cannot predict every complication that might appear over years or across a much larger population.

The ANGPTL3 results should therefore be viewed as an important early signal rather than a finished medical breakthrough. Four people receiving the highest dose experienced major cholesterol reductions that remained after more than a year, but many questions remain unanswered.

If future trials confirm the findings, doctors may eventually have a new option for people whose cholesterol remains dangerously high despite conventional treatment. Until then, existing medications and established treatment plans remain the standard tools for managing cardiovascular risk.

The remarkable part of this research is that the question has changed. Scientists are no longer simply wondering whether a one-time genetic treatment for severe cholesterol is imaginable. They are testing it in real patients, measuring the results, and preparing for the much larger trials that will decide whether the approach has a future in medicine.