Scientists are testing a potential “one-time” approach to lowering the cholesterol that drives plaque buildup in arteries, by using gene-editing tools designed to alter liver cells. The work is at an early stage, with results reported from only a few dozen people so far, and researchers emphasized that bigger studies are needed before anyone can rely on the treatment to prevent heart attacks.
The goal centers on LDL cholesterol, often described as the “bad” kind. Too much LDL can build plaque in artery walls and is a main driver of heart attacks and strokes, the Associated Press reported. Cardiovascular disease is the leading killer in the United States and worldwide, and the research interest reflects the limits of current care for many patients.
In the United States and elsewhere, millions take cholesterol-lowering medicines such as statins, which block part of the liver’s production of cholesterol. But some people struggle to get LDL low enough and may discontinue drugs because of side effects, keeping pressure on researchers to find a different strategy.
Gene-editing researchers said they are drawing on “natural experiments” that show what happens when certain genes are not functioning. The AP described earlier reports of rare mutations in people who have very high LDL because of differences in how cholesterol is managed, along with cases where extremely low LDL appears to be driven by genetic changes.
The AP reported that Dr. Kiran Musunuru, a cardiologist now at the University of Pennsylvania, previously described a mutation involving a gene named ANGPTL3. In people with that natural change, LDL cholesterol and triglycerides were reported to be lower. Separately, geneticists at UT Southwestern Medical Center found that some people’s extremely low LDL cholesterol is due to loss of function of another gene, PCSK9.
Scientists involved in the new trials said their efforts aim to mimic those genetic effects by directly switching off the relevant targets in liver cells. “It’s a natural experiment in what would happen if we actually changed the gene,” said Dr. Steven Nissen, of the Cleveland Clinic, who with Dr. Luke Laffin oversaw an ANGPTL3 study funded by Swiss-based CRISPR Therapeutics.
In one early study described by the AP, 15 adults received a single infusion of tiny particles carrying the CRISPR tool to the liver, switching off the ANGPTL3 gene inside liver cells. Laffin and Nissen reported in November that within two weeks, participants receiving the highest dose saw LDL and triglyceride levels both drop by half.
The AP also reported early results from Boston’s Verve Therapeutics, a subsidiary of pharmaceutical giant Eli Lilly. Verve’s PCSK9-targeted editing infusion “cut LDL cholesterol by a similar amount” in a small study, according to the AP. Both companies’ initial studies were conducted in Australia, the U.K. and other countries, and the AP said U.S. study sites are opening as additional trials are planned.
While gene editing is considered permanent in principle, researchers cautioned that durability and safety must be proven in larger populations and over longer follow-up. Penn’s Musunuru said that in an earlier Verve study, some participants had been tracked for two years and that their cholesterol remained lowered. Still, Dr. Joseph Wu of Stanford University, who was not involved in either study, said there are major safety questions to be answered, including long-term safety for CRISPR-based therapies and whether the particles deliver effects only to the intended target.
Wu warned that CRISPR-based therapies for any disease have not been used enough to know long-term safety, and he also said the particles carrying the gene-editing tool can irritate or inflame the liver. Another uncertainty, the AP reported, is whether gene editing affects only the intended target.
Because those risks remain unresolved, the AP said the early studies largely target people at very high risk. Even as researchers work toward more definitive trials, the American Heart Association’s guidance still applies broadly to most people—gene editing aside—including eating a heart-healthy diet, staying physically active, maintaining a healthy weight, quitting smoking, and getting enough sleep.
On the medical side, the association recommends controlling blood pressure and keeping diabetes under control. For cholesterol, the AP reported that keeping LDL around 100 is considered fine for healthy people, but for those with high cholesterol or existing heart disease, guidelines recommend lowering LDL to at least 70, even lower for people at very high risk. When lifestyle changes are not enough, statin pills such as Lipitor and Crestor, along with generic equivalents, are described as highly effective at lowering LDL; the AP also noted other pill and injected options for some patients.