In base editing’s first clinical test, researchers last year engineered donated immune cells in a dish to target a teenager’s leukemia, then infused them to put her disease into remission so she could get a stem cell transplant. In the Verve trial, however, the editing took place inside the body, specifically in the liver, a relatively easy organ to target because it sucks up foreign particles.
The trial subjects have a disease called heterozygous familial hypercholesterolemia (FH), usually caused by a defect in one copy of a gene that encodes a cell surface protein needed by the liver to clear the blood of low-density lipoproteins (LDLs), the “bad” cholesterol. People with FH must take daily statins and other drugs to control their cholesterol levels, but many struggle to keep to the lifelong regimen. Without any treatment, many would suffer heart attacks or strokes by age 50.
FH patients still make some LDL receptors, and Verve’s strategy is to keep those molecules around for longer by altering the liver’s gene for PCSK9, an enzyme that normally removes the receptors from cells. Its treatment consists of messenger RNA (mRNA) that instructs cells to manufacture the gene editor’s protein components. Packaged in tiny balls of fat called lipid nanoparticles—also used in the mRNA COVID-19 vaccines—it travels to the liver, where an additional RNA strand also carried in the particles guides the base editor to the gene for PCSK9. The combo makes a one–base pair change so that cells can produce only shortened, nonfunctional versions of the enzyme.
In three patients receiving the highest doses of the base editor, blood levels of functioning PCSK9 protein dropped between 47% and 84% and LDL levels have fallen between 39% and 55% for as long at 6 months. This is roughly comparable to the drop in LDL in patients given relatively new, injected PCSK9-blocking drugs, which some patients now take instead of statins.
However, two patients who already had severely blocked arteries had heart problems after the base editor infusion. One died from cardiac arrest, a case that Verve says a safety board found was unrelated to the Verve infusion. The other person survived a heart attack, but it came just a day after treatment and could have been related. The man, however, had chest pains prior to the trial that he didn’t mention. “Had he reported the symptoms to the investigators, he would not have been enrolled,” Verve CEO Sek Kathiresan says.
Some clinicians are also concerned about another potential risk of base editing. They note that like standard CRISPR, it could make changes to other, nontargeted genes. Endocrinologist Anne Goldberg of the Washington University School of Medicine in St. Louis, who treats FH patients, says that although the Verve treatment “could be a game changer,” she wants to see more safety data. “CRISPR in humans makes me a bit nervous,” she says.
Verve plans to test its treatment in a total of about 40 FH patients. Current participants are in New Zealand and the United Kingdom, but U.S. regulators recently cleared the way for testing after the company produced data indicating the editor would not alter DNA in sperm and egg cells. It expects to compare the approach with a placebo in a larger trial starting in 2025.
The company hasn’t detailed how much it would charge for the treatment, but Kathiresan has said it will be more affordable than some of the gene therapies with million-dollar price tags. He says the PCSK9 base editor could one day be used to treat people who don’t have FH but have early heart disease. It could even be given widely to older adults to ward off disease. “Down the road, maybe you turn 50, and this is what you get and it prolongs your life,” he says. “That’s the ultimate vision.”
The wait, however, could be long.
