CRISPR Slashes ‘Bad Cholesterol’ Levels by 95 Percent in Early Results

The gene editor CRISPR is tackling fatty molecules in the body that contribute to one of the world’s top killers: cardiovascular disease.

At the American Heart Association Scientific Sessions 2025 (AHA 2025) this month, Scribe Therapeutics, a startup based in Alameda, California, presented three CRISPR formulations that slashed dangerously high lipid levels in lab-grown cells, mice, and monkeys.

With a single injection, their flagship formulation lowered “bad cholesterol” levels in primates for over 515 days. The treatment used a type of genetic manipulation called epigenome editing that doesn’t directly change the genetic code, potentially reducing side effects.

Two other CRISPR formulations targeted lipoprotein(a) and triglycerides, both fatty substances that form clumps inside blood vessels when at high levels. An injection in mice slashed the molecules by over 95 percent in early trials.

The therapies join other emerging efforts using CRISPR to tackle cardiovascular disease. If the results translate to humans, a daily pill—often taken for decades—may become a thing of the past.

“These results demonstrate that comprehensive engineering of CRISPR technologies can produce medicines with markedly improved safety and performance, surpassing the limitations of early Cas9-based systems,” Benjamin Oakes, cofounder and CEO of Scribe, said in a press release.

A Hefty Problem

High cholesterol haunts millions of Americans. A silent killer, the fatty molecules clog up blood vessels and raise the risk of heart attack, vascular disease, and stroke. Physicians recommend daily statins and dietary changes to manage cholesterol levels, but the regime is hard to follow—especially for years or decades.

Cholesterol comes in multiple forms. Some of these protect the heart and blood vessels. Others lead to clogged arteries. LDL, or low-density lipoprotein, normally transports molecules from the liver to the body’s cells to maintain essential functions, such as building membranes, producing hormones, and creating vitamin D. Too much LDL, however, leads to a buildup of plaques that harden blood vessels and narrow their diameter. This means the heart must work harder to pump blood through the body.

After years of research, scientists identified a gene called PCSK9 that, if overactive, increases the levels of LDL circulating in the blood. FDA-approved drugs that inhibit the PCSK9 protein show promise for lowering cholesterol. But inhibiting the gene itself could offer a longer-term solution.

There have been early successes. In 2023, a small clinical trial in people genetically prone to dangerously high levels of cholesterol found a single infusion of a precise gene editor decreased artery-clogging fat by almost half. Participants had a single mutated DNA letter in the PCSK9 gene that caused their LDL levels to skyrocket. Using base editing—a version of CRISPR—the team engineered a therapy to correct the genetic typo.

A similar strategy could also benefit other populations with high cholesterol. However, base editing permanently alters the genome and could trigger unexpected DNA changes.

Enter epigenetic editors. Rather than directly altering DNA letters, this technology targets the molecular machinery that switches genes on or off. Because epigenetic editors don’t directly change the genetic code, the approach could potentially be safer than gene editing.

Last year, one team employed designer molecules called zinc-finger proteins, a favorite gene-editing tool predating CRISPR, to shut down PCSK9 without changing the gene itself. A single injection slashed cholesterol levels in mice and kept them low for nearly a year—roughly half the mice’s lifespan.

AHA 2025 built on those results.

Scribe developed an epigenetic silencer to suppress PCSK9 using CRISPR-CasX. Like the original version, CRISPR-Cas9, CRISPR-CasX has a guide RNA that tethers CasX—a tiny scissor enzyme—to genes involved in regulating PCSK9 activity and shuts them down.

In monkeys, a single infusion of the treatment slashed LDL levels up to 68 percent. Unlike DNA edits, epigenetic modifications are often lost when cells divide, meaning the drug could lose efficacy over time, especially in rapidly regenerating organs like the liver. But the monkey’s LDL levels remained low for over 515 days without otherwise stressing their livers. Also, the drug didn’t notably change the activity of other genes in cultured human liver cells, suggesting it’s precise.

The data strengthens “the case for a new class of durable epigenetic medicines for large patient populations,” wrote the company in a press release.

Trio of Trouble

PCSK9 isn’t the only gene involved in heart disease. CRISPR Therapeutics, headquartered in Switzerland, worked with the Cleveland Clinic Foundation to find another gene related to high cholesterol levels: ANGPTL3. Studies show people born with dysfunctional versions of the gene naturally have lower LDL levels and risk of heart disease.

The team used CRISPR-Cas9 to disable the gene and recruited 15 people with various blood lipid diseases to test the treatment’s safety profile. Two weeks after a shot, participants’ ANGPTL3 protein and LDL levels dropped significantly and remained low for at least 60 days. Results from the trial, also presented at AHA 2015, found that the treatment was well tolerated overall.

“This is really unprecedented,” said author Luke J. Laffin in a press briefing. “If confirmed in larger trials, this one-and-done approach could transform care for people with lifelong lipid disorders and dramatically reduce cardiovascular risk.”

Artery-blocking lipids beyond LDL are now also in CRISPR’s crosshairs.

Lipoprotein(a) is a mysterious nanoball of fat that’s somewhat similar to LDL in structure but with a more complex mix of components. The substance deposits cholesterol as it roams blood vessels—including smaller ones involved in healing and regeneration. An estimated 30 percent of people worldwide have abnormally high levels of lipoprotein(a). This is mainly due to genetic risks and is hard to reverse with dietary changes or medication.

Another CRISPR-based technology is showing promise here. At the conference, Scribe said its in-house CasXE gene editor inactivates a gene that makes Lp(a) in liver cells. In mice, a single injection slashed levels of the fatty balls by up to 95 percent, with no detectable off-target editing.

Finally, the company showcased a different CasXE gene editor that kneecaps a gene associated with lipid production. Like other genetic targets, people with naturally lower levels of the gene APOC3 have low levels of blood lipids and lower risk of heart disease. One shot edited over 75 percent of all liver cells in monkeys and almost completely reversed high blood lipid levels in mice.

These are all preliminary results, but they could lead to a quantum shift in managing a global chronic disease with a single shot instead of daily pills.