How Gene Editing Could Help Solve the Problem of Poor Cholesterol

Cardiovascular disease is the leading cause of death in the U.S. and around the world. Though it’s held the top spot for decades, it wasn’t always the king of mortal maladies. Its ascension was propelled by two of medical science’s greatest successes.

“Before the 20th century, heart disease was an uncommon cause of death,” says Dr. Michael Shapiro, a professor of cardiology at the Wake Forest University School of Medicine. Bacterial infections such as tuberculosis and dysentery, as well as smallpox and other contagious viruses, were common killers. “Antibiotics and vaccines changed everything.”

Some experts believe that gene editing using CRISPR technologies could be medical science’s next big breakthrough—an advancement that allows the human race to smash through the longevity ceiling imposed by heart disease, and maybe also other common killers. One day, hopefully, “CRISPR technology could be used to treat many conditions, for example neurological disease, cancers, and cardiovascular disease,” says Dr. Qiaobing Xu, a gene-editing researcher and professor of biomedical engineering at Tufts University.

Perhaps the most tantalizing of these applications involves lowering cholesterol, specifically the “bad” kind: low-density lipoprotein (LDL) cholesterol. “While cholesterol is an essential molecule for myriad biological processes, if blood levels of LDL cholesterol get too high, the cholesterol can accumulate on the walls of the arteries, forming congestive deposits known as plaques,” Shapiro says. These plaques directly cause or contribute to many forms of cardiovascular disease. “Managing cholesterol is a huge part of my job as a cardiologist focused on prevention.”

While a poor diet, stress, lack of exercise, and other lifestyle factors can lead to cholesterol problems, genetic factors also play a role. Some genes that regulate blood levels of LDL cholesterol appear to be good targets for CRISPR gene-editing technologies. Already, research in non-human primates has found that editing cholesterol genes appears to be both safe and effective for the mitigation of cardiovascular disease. And, earlier this year, the first human underwent gene editing for the treatment of high cholesterol.

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The science underlying CRISPR and gene editing for LDL cholesterol is rapidly advancing. However, some major hurdles remain, and experts warn of the potential for unanticipated risks.

The science of gene editing for cholesterol

CRISPR is an acronym for clustered regularly interspaced short palindromic repeats. These are segments of DNA found in some types of bacteria. These segments act like storage containers for snippets of genetic material cut from defeated viral pathogens. The bacteria store these snippets in order to enhance their innate immunity from future threats.

During the past decade, researchers have figured out how to harness these CRISPR-related biological processes to edit the genetic material of living organisms, including people. “Gene editing involves two pieces,” Xu says. There’s an endonuclease—an enzyme—that performs the genetic alteration, and there’s also a guide RNA that ensures the endonuclease is only working on the desired part of the genome. “You put those two pieces together, and you can modify the genome,” he says.

Sometimes a third piece is necessary: As Xu says, some forms of gene editing are done ex vivo, or outside the body. The relevant cells are removed and genetically modified in a lab. They’re then put back into the same person so that they can multiply and displace the old unedited cell type. This ex vivo process can be used to change the genetic material of blood cells, for example, and has been utilized to treat conditions such as sickle cell disease.

But a second, more complex method of gene editing involves in vivo alterations to a person’s genetic material. This is necessary when the relevant material cannot be removed—for example, when it’s housed in an organ. In these instances, a delivery vehicle is needed to safely carry the injected CRISPR technology to the correct location inside the human body. Xu was part of a team that published groundbreaking research in 2021 in the Proceedings of the National Academy of Sciences. That research identified a specific type of lipid nanoparticle that could carry CRISPR gene-editing material specifically to the liver, which is the site of the modifications needed to address cholesterol problems.

The ability to edit genetic material is only useful if you’ve identified DNA sequences or mutations that directly contribute to the development of health problems. In the case of LDL cholesterol, researchers believe they’ve identified two such targets. The discovery of those involved nifty deductions that would make Sherlock Holmes proud.

“About 20 years ago, there was a research group in France that was studying a number of French families that had a relatively common inherited condition called familial hypercholesterolemia, or FH,” Shapiro says. People with FH have unusually high levels of LDL cholesterol from birth and, as a consequence, are at high risk for premature cardiovascular disease. However, the French kindred did not have any mutations in the known FH genes. The French researchers, working with another team in Montreal, Canada, identified a specific problem mutation in this kindred. The mutation causes a protein known as PCSK9 to bind to receptors that would normally help remove LDL cholesterol from the blood. “The vast majority of the time, mutations make a protein that a gene encodes for less effective, and this is called a loss-of-function mutation,” he says. “But in this French kindred, it turned out that the PCSK9 gene mutation was a gain-of-function mutation.”

Because such mutations are uncommon, researchers who looked at this work theorized that some people might be born with its opposite—that is, a loss-of-function mutation on the PCSK9 gene. Theoretically, such a mutation would lower levels of blood cholesterol and cardiovascular disease. “They looked for this in large populations, and sure enough, they found a naturally occurring loss-of-function mutation that reduces LDL cholesterol and makes people almost immune to atherosclerosis,” Shapiro says.

The discovery of the PCSK9 gene and the protein’s role in hypercholesterolemia led to the development of PCSK9 inhibitors, a class of cholesterol drugs designed to limit PCSK9 activity. But this discovery also provided a perfect target for CRISPR gene-editing therapies. Here was a mutation that occurs naturally, and that lowers LDL cholesterol. Just as importantly, the mutation wasn’t associated with any known health problems. All of this suggests that using CRISPR technologies to make such a modification could be both safe and effective. “Researchers saw all this with the PCSK9 gene and started saying yes, CRISPR therapy makes sense,” he says.

Researchers, including Xu, have since identified a second gene—Angptl3—that plays an important role in regulating blood levels of cholesterol and triglycerides. “If we can knock down both of those two proteins—PCSK9 and Angptl3—that should lead to lower lipid and cholesterol levels in plasma, and that can decrease the risk of cardiovascular disease,” Xu says.

Read More: How to Lower Your Cholesterol Naturally

Potential pitfalls

Thus far, the research on CRISPR and its cholesterol-lowering genetic targets has been nothing short of revolutionary. Most observers applaud the science and express enthusiasm about its possibilities. But most also temper their enthusiasm with realism—and some concerns.

“One of the big challenges is going to be proving safety and specificity in humans,” says Dr. Christie Ballantyne, chief of cardiology and cardiovascular research at Baylor College of Medicine. “You’re talking about making a permanent change to someone’s DNA, and there are concerns that any negative effects may take a long time to show up.”

The initial clinical trials (including those already planned or in progress) will include people with serious inherited cholesterol disorders—cases where the pros and cons clearly favor gene-editing therapy. However, the big hope is that this treatment could eventually be performed as a preventive measure—before someone has lived for years or decades with elevated levels of cholesterol. That means going inside a relatively healthy person and performing fine-tuned work on very specific parts of their DNA. In essence, it’s like putting out a small fire that is likely to spread—but hasn’t spread yet. And any time you play with fire, someone may get burned. “You need to specifically silence some genes and not others, which is not easy,” Xu says. “Caution is needed, and the concerns people have are valid.”

Even if all the promising research pans out and the therapy works, there are reasons to question how broadly it will be embraced.

“We already have some monoclonal antibody therapies that target PCSK9 that are very effective,” Ballantyne says. Statins, which for years have been the go-to treatment for people with moderate or severe cholesterol problems, have also proven to be both safe and effective. They’re also cheap. (Shapiro advocates for their wider deployment. “There’s a lot of misinformation out there on statins,” he says. “While they can cause nuisance side-effects like muscle aches and pain in a minority of patients, they’re one of the most scrutinized drugs, and they’ve turned out to be extremely safe.”)

“Let’s say you’re 40, your cholesterol is really high, and your choice is between a statin that’s supported by studies with hundreds of thousands of users, or gene editing, which will permanently change something in your liver,” Ballantyne says. “I think most people are going to pick the statin.”

On the other hand, one of the biggest issues with the cholesterol drugs we have today is that, even though they work, some people won’t take them. “I can’t even get some people who have had a heart attack to stay on statins,” Shapiro says. “About 50% of users stop taking them within a year, and after five years, only about 5% of users are still on them.”

The issue of poor medication adherence is a common and intractable one throughout the field of medicine. There’s reason to believe that if people were convinced of its safety, a one-time gene-editing treatment would be very appealing when compared to taking a daily pill for the rest of their lives.

Read More: What to Know About High Cholesterol in Kids

Why CRISPR is not going anywhere

Almost across the board, experts say that gene-editing therapy is likely here to stay. “It’s great science, and I think the technology is going to happen,” Ballantyne says.

He recalls that, when he was in medical school, monoclonal antibody therapy was the hot new thing. Back then it had plenty of naysayers, but they were silenced long ago. “It took a couple decades and there were problems along the way, but now it’s everywhere.” He thinks gene editing is likely to follow a similar path.

However, Ballantyne says that cholesterol may prove more resistant to CRISPR-based treatments than some other medical conditions. “If someone has a lethal genetic disease with no treatment, that’s a more straightforward risk-benefit calculation,” he says. “With cholesterol, I think that might not be such an easy shot on goal.”