Gene Silencing Slashes Cholesterol in Mice—No Gene Edits Required

With just one shot, scientists have slashed cholesterol levels in mice. The treatment lasted for at least half their lives.

The shot may sound like gene editing, but it’s not. Instead, it relies on an up-and-coming method to control genetic activity—without directly changing DNA letters. Called “epigenetic editing,” the technology targets the molecular machinery that switches genes on or off.

Rather than rewriting genetic letters, which can cause unintended DNA swaps, epigenetic editing could potentially be safer as it leaves the cell’s original DNA sequences intact. Scientists have long eyed the method as an alternative to CRISPR-based editing to control genetic activity. But so far, it has only been proven to work in cells grown in petri dishes.

The new study, published this week in Nature, is a first proof of concept that the strategy also works inside the body. With just a single dose of the epigenetic editor infused into the bloodstream, the mice’s cholesterol levels rapidly dropped, and stayed low for nearly a year without notable side effects.

High cholesterol is a major risk factor for heart attacks, strokes, and blood vessel diseases. Millions of people rely on daily medication to keep its levels in check, often for years or even decades. A simple, long-lasting shot could be a potential life-changer.

“The advantage here is that it’s a one-and-done treatment, instead of taking pills every day,” study author Dr. Angelo Lombardo at the San Raffaele Scientific Institute told Nature.

Beyond cholesterol, the results showcase the potential of epigenetic editing as a powerful emerging tool to tackle a wide range of diseases, including cancer.

To Dr. Henriette O’Geen at the University of California, Davis, it’s “the beginning of an era of getting away from cutting DNA” but still silencing genes that cause disease, paving the way for a new family of cures.

Leveling Up

Gene editing is revolutionizing biomedical science, with CRISPR-Cas9 leading the charge. In the last few months, the United Kingdom and the US have both given the green light for a CRISPR-based gene editing therapy for sickle cell disease and beta thalassemia.

These therapies work by replacing a dysfunctional gene with a healthy version. While effective, this requires cutting through DNA strands, which could lead to unexpected snips elsewhere in the genome. Some have even dubbed CRISPR-Cas9 a type of “genomic vandalism.”

Editing the epigenome sidesteps these problems.

Literally meaning “above” the genome, epigenetics is the process by which cells control gene expression. It’s how cells form different identities—becoming, for example, brain, liver, or heart cells—during early development, even though all cells harbor the same genetic blueprint. Epigenetics also connects environmental factors—such as diet—with gene expression by flexibly controlling gene activity.

All this relies on myriad chemical “tags” that mark our genes. Each tag has a specific function. Methylation, for example, shuts a gene down. Like sticky notes, the tags can be easily added or removed with the help of their designated proteins—without mutating DNA sequences—making it an intriguing way to manipulate gene expression.

Unfortunately, the epigenome’s flexibility could also be its downfall for designing a long-term treatment.

When cells divide, they hold onto all their DNA—including any edited changes. However, epigenetic tags are often wiped out, allowing new cells to start with a clean slate. It’s not so problematic in cells that normally don’t divide once mature—for example, neurons. But for cells that constantly renew, such as liver cells, any epigenetic edits could rapidly dwindle.

Researchers have long debated whether epigenetic editing is durable enough to work as a drug. The new study took the concern head on by targeting a gene highly expressed in the liver.


Meet PCSK9, a protein that keeps low-density lipoprotein (LDL), or “bad cholesterol,” in check. Its gene has long been in the crosshairs for lowering cholesterol in both pharmaceutical and gene editing studies, making it a perfect target for epigenetic control.

“It’s a well-known gene that needs to be shut off to decrease the level of cholesterol in the blood,” said Lombardo.

The end goal is to artificially methylate the gene and thus silence it. The team first turned to a family of designer molecules called zinc-finger proteins. Before the advent of CRISPR-based tools, these were a favorite for manipulating genetic activity.

Zinc-finger proteins can be designed to specifically home in on genetic sequences like a bloodhound. After screening many possibilities, the team found an efficient candidate that specifically targets PCSK9 in liver cells. They then linked this “carrier” to three protein fragments that collaborate to methylate DNA.

The fragments were inspired by a group of natural epigenetic editors that spring to life during early embryo development. Relics of past infections, our genome has viral sequences dotted throughout that are passed down through generations. Methylation silences this viral genetic “junk,” with effects often lasting an entire lifetime. In other words, nature has already come up with a long-lasting epigenetic editor, and the team tapped into its genius solution.

To deliver the editor, the researchers encoded the protein sequences into a single designer mRNA sequence—which the cells can use to produce new copies of the proteins, like in mRNA vaccines—and encapsulated it in a custom nanoparticle. Once injected into mice, the nanoparticles made their way into the liver and released their payloads. Liver cells rapidly adjusted to the new command and made the proteins that shut down PCSK9 expression.

In just two months, the mice’s PCSK9 protein levels dropped by 75 percent. The animals’ cholesterol also rapidly decreased and stayed low until the end of the study nearly a year later. The actual duration could be far longer.

Unlike gene editing, the strategy is hit-and-run, explained Lombardo. The epigenetic editors didn’t stay around inside the cell, but their therapeutic effects lingered.

As a stress test, the team performed a surgical procedure causing the liver cells to divide. This could potentially wipe out the edit. But they found it lasted multiple generations, suggesting the edited cells formed a “memory” of sorts that is heritable.

Whether these long-lasting results would translate to humans is unknown. We have far longer lifespans compared to mice and may require multiple shots. Specific aspects of the epigenetic editor also need to be reworked to better tailor them for human genes.

Meanwhile, other attempts at slashing high cholesterol levels using base editing—a type of gene editing—have already shown promise in a small clinical trial.

But the study adds to the burgeoning field of epigenetic editors. About a dozen startups are focusing on the strategy to develop therapies for a wide range of diseases, with one already in clinical trials to combat stubborn cancers.

As far as they know, the scientists believe it’s the first time someone has shown a one-shot approach can lead to long-lasting epigenetic effects in living animals, Lombardo said. “It opens up the possibility of using the platform more broadly.”

Image Credit: Google DeepMind / Unsplash

Shelly Fan
Shelly Fan
Shelly Xuelai Fan is a neuroscientist-turned-science writer. She completed her PhD in neuroscience at the University of British Columbia, where she developed novel treatments for neurodegeneration. While studying biological brains, she became fascinated with AI and all things biotech. Following graduation, she moved to UCSF to study blood-based factors that rejuvenate aged brains. She is the co-founder of Vantastic Media, a media venture that explores science stories through text and video, and runs the award-winning blog Her first book, "Will AI Replace Us?" (Thames & Hudson) was published in 2019.
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