Gene Editing Technology Could Treat Hypercholesterolemia

On Sunday, November 12, 2023, Verve Therapeutics presented the results of an ongoing clinical trial using gene therapy to treat uncontrolled high cholesterol, atherosclerotic cardiovascular disease, and heterozygous familial hypercholesterolemia at the American Heart Association meeting in Philadelphia.

According to the press release from the company, a proof-of-concept study has proven that the in vivo base editing gene therapy can reduce low-density lipoprotein cholesterol (LDL-C) and proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) blood protein levels.

LDL is sometimes called “bad” cholesterol because elevated LDL levels are linked to an increased risk of heart disease and stroke as it can build up, causing plaque to accumulate in the walls of the blood vessels.

The Mayo Clinic notes that a gain of function mutations in the PCSK9 gene increases protein expression, which is thought to impact the expression of LDL receptors on the surface of the liver, impairing LDL-C degradation and clearing. This causes the circulating LDL-C levels in the bloodstream to increase.

Based on the genetic understanding of high cholesterol, Verve developed VERVE-101, a single-dose delivered via intravenous infusion to inactivate the PCSK9 gene in the liver. The intention was to improve LDL-C degradation and clearance, reducing blood LDL-C levels.

In a press release, the team at Verve revealed that patients treated with VERVE-101 achieved an LDL-C reduction of up to 55%. Additionally, the treatment reduced PCSK9 protein expression by up to 84%. The data suggested that increasing the dose in each infusion could produce more pronounced physiological changes.

Additionally, the company concluded that the product has a safety profile that warrants further exploration and research. Participants who received a lower treatment dose did not have any side effects. Meanwhile, those receiving a higher dose experienced transient mild to moderate infusion reactions and asymptomatic increases in liver transaminases.

Furthermore, two patients had severe adverse reactions. One experienced fatal cardiac arrest, and the other had a myocardial infarction. However, the company maintains that the adverse events throughout the study were not linked to the treatment.

“Our goal is to fundamentally disrupt the chronic care model for cardiovascular disease and provide a new single-course treatment option for patients,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve, in the press release. “These data confirm our hypothesis that a single-course gene editing medicine has the potential to induce meaningful and durable reductions in LDL-C when administered at therapeutic doses. Based on the favorable initial findings in the heart-1 trial, we are continuing to enroll patients in the potentially therapeutic dose cohorts. And with the recent clearance of the United States investigational new drug (IND) application for VERVE-101, we look forward to expanding our clinical trial into the US.”