The treatment uses a newer, more precise form of Crispr called base editing to inactivate a gene in the liver called PCSK9. This gene plays a critical role in controlling LDL cholesterol in the blood. Instead of cutting genes, as Crispr is designed to do, base editing simply swaps one DNA letter for another. Verve’s treatment is designed to change an A to a G, which effectively turns the PCSK9 gene off.
In a study published in the journal Circulation earlier this year, researchers from the company showed that the approach lowered bad cholesterol 49 to 69 percent in monkeys, depending on the dosage they received. Those reductions have now lasted two and a half years following a single dose of the therapy.
The current trial is for patients with familial hypercholesterolemia, a type of inherited high cholesterol that affects around 3 million people in the United States and Europe, combined. While the participants already had severe coronary artery disease, and some had previously experienced a heart attack, the company aims to eventually treat younger patients in order to prevent these outcomes. “We’re envisioning that this will ultimately be a treatment that could be applied earlier in the disease course to younger patients who have very high lifetime risks,” Bellinger said.
Sanjay Rajagopalan, director of the Cardiovascular Research Institute at Case Western Reserve University School of Medicine, calls the results a “very exciting” proof of concept. But Rajagopalan, who wasn’t involved in the Verve study, says the main concern about any Crispr-based approach is the potential for off-target effects, in which unwanted cells or genes would unintentionally be edited.
“This is a gene editing study. You’re changing the genome forever,” said Watson, echoing the same point. “Safety is going to be of the utmost importance.”
During the press conference, Bellinger said the company has not detected any off-target editing in human liver cells treated with its experimental therapy. He said unwanted genetic edits could potentially cause health problems such as cancer, although he believes the risk is very low. “Ultimately, we will have to run those larger studies with observation for those outcomes,” he said.
Verve Therapeutics plans to enroll more patients in the trial next year, including in the US. In November 2022 the US Food and Drug Administration put a pause on the trial’s start, asking for more information on the possibility of off-target edits in other cells and whether the gene edit could be passed down to children whose parents get the therapy. But the agency lifted the hold in October, allowing the company to begin enrolling patients in the US.
And like any novel therapy, Rajagopalan points out, “the treatment would have to compete with other safe treatment approaches that are already available.” For instance, statins and other lipid-lowering drugs are known to be safe and effective. “However,” he continues, “the convenience of one treatment that can fix the disorder permanently is extremely attractive.”