Cholesterol-Lowering Gene Therapy Shows Early Promise

New research seems to show the potential of a CRISPR-based gene therapy meant to neuter certain forms of cardiovascular disease. In the world’s first human trial of the therapy, people given the highest doses experienced significant and long-lasting reductions in their low-density lipoprotein cholesterol (LDL-C). The treatment could be used to help people genetically predisposed to high LDL-C and its accompanying health risks.

The gene therapy is being developed by the company Verve Therapeutics under the code name VERVE-101, in collaboration with Eli Lilly. It uses CRISPR technology to turn off a gene found in liver cells that produces an enzyme responsible for regulating LDL, called PCSK9.

In some people with familial hypercholesterolemia (high cholesterol), their PCSK9 gene is altered in a way that leads to much higher levels of LDL-C circulating in the blood. This excess “bad” cholesterol can then build up along the walls of our arteries and organs as plaque, greatly raising the risk of having heart attacks, stroke, and other cardiovascular problems, often at an earlier age than usual. By turning off PCSK9, the hope is that VERVE-101 will reliably and durably reduce LDL-C levels in people with this condition.

The small trial involved nine people with familial hypercholesterolemia caused by having one copy of a dysfunctional PCSK9 gene. Each person received a single infusion of VERVE-101, though some got higher doses than others.

Phase I trials are mainly intended to test the safety of an experimental treatment. The drug did appear to be generally well-tolerated, with most adverse events being mild and likely unrelated to the treatment, according to the study researchers. In the three participants who received the highest doses of VERVE-101, the researchers also found clear reductions in their LDL-C levels a month later, with the highest dose patient still showing reduced LDL-C six months later.

That said, two people did experience serious adverse events during the trial: one person experienced a heart attack a day after treatment and another a fatal cardiac arrest five weeks later. An independent safety panel ruled that the heart attack may have been connected to the treatment, but that the cardiac arrest was caused by the participant’s underlying heart problems; the panel ultimately recommended that the trial go on.

The team’s findings were presented this past weekend at the American Heart Association’s Scientific Sessions 2023.

“Instead of daily pills or intermittent injections over decades to lower bad cholesterol, this study reveals the potential for a new treatment option—a single-course therapy that may lead to deep LDL-C lowering for decades,” said senior study author Andrew Bellinger, chief scientific officer at Verve Therapeutics, in a statement released on Sunday by the AHA.

These results are still very preliminary, so they should be viewed with added caution. Much larger trials following people over a longer period of time will be needed to truly confirm whether VERVE-101 can actually lower people’s risk of heart disease and its overall safety, but the promise of this therapy is certainly exciting. Animal studies have suggested that its LDL-lowering effect can last for at least 2.5 years and possibly for a lifetime. Currently, there are about 1.3 million adults and children in the U.S. estimated to have a form of familial hypercholesterolemia that could be treated with this therapy, according to the AHA.

Verve plans to keep enrolling more patients in the phase I trial to receive the highest doses of VERVE-101 up through early next year; it will also start a second phase I trial in 2024 testing out the therapy with a different delivery method (VERVE-102). Should this research go as expected, the company is expected to launch a randomized, placebo-controlled phase 2 clinical trial of the best-performing version in 2025.

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