Experimental treatment for high cholesterol edits DNA in the body to reduce LDL

An experimental gene therapy for high cholesterol is showing promise in clinical trials and inching closer to approval.

The treatment, called VERVE-102, is being tested in people with familial hypercholesterolemia (FH), an inherited condition that raises the levels of low-density lipoprotein (LDL) cholesterol — the "bad" kind — in the blood. It's also being tested in people with premature coronary artery disease (CAD), in which the arteries narrow and can't deliver enough oxygenated blood to heart muscle. The age at which CAD is considered "premature" varies, but it generally occurs before age 65 in women and age 55 in men.

Both groups "require deep and durable reductions" of LDL in the blood, Verve Therapeutics, the treatment's maker, noted in an April statement. In an ongoing clinical trial, the company tested the treatment in 14 people with FH and/or premature CAD, and found that a single dose of the therapy led to a 53% reduction in LDL, on average.

These early data are drawn from three groups of people who received different doses of the treatment. The four participants given the highest dose saw the largest benefit: a 69% reduction in LDL, at maximum.

Across the groups, "VERVE-102 was well-tolerated, with no treatment-related serious adverse events (SAEs) and no clinically significant laboratory abnormalities observed," Verve's statement noted.

VERVE-102 uses a modified version of CRISPR, the famous gene-editing system. The CRISPR systems developed originally introduce a "break" in both strands of a DNA molecule, and then, the cell's built-in repair system swoops in to repair the break. However, this comes with the risk of adding unwanted mutations to the DNA.

Related: New CRISPR alternative can 'install' whole genes, paving the way to treatment for many genetic disorders

The new cholesterol-lowering therapy instead uses "base editing," which swaps out just one letter in DNA's code, thus sidestepping the danger of a double-stranded break. Like classic CRISPR, the base editor still includes a "guide" molecule to fix its aim at the correct gene, and from there, an enzyme tweaks just one letter in DNA's code.

VERVE-102 targets a gene called PCSK9, which controls the number of LDL receptors on the surfaces of cells. The quantity of these receptors dictates how quickly LDL gets cleared from the blood. When PCSK9 is too active — as it is in the genetic disease FH — it breaks down LDL receptors before they can make it to the cell surface, thus causing LDL to accumulate in the bloodstream instead.

The new therapy, given in a single intravenous infusion over two to four hours, is designed to turn off PCSK9, especially in the liver, where LDL receptors are abundant. Across the three dosing groups, there was a decrease in both PCSK9 activity and LDL levels in the 28 days following the treatment, with higher doses tied to greater reductions.

Now, the company is enrolling a fourth group of patients who will receive an even higher dose, and who are being recruited in the United Kingdom, Canada, Israel, Australia and New Zealand. As of April, two people in the group had been treated.

Verve expects to release data from this portion of the trial later this year, as well as start its next clinical trial, which will include more participants. The next trial will likely enroll U.S. participants, as the Food and Drug Administration granted the therapy "Fast Track Designation" to help expedite its development and approval.

Notably, in June, Verve was acquired by the drug company Lilly, which aims to continue the development of the treatment.

"VERVE-102 has the potential to be the first in vivo [in the body] gene editing therapy for broad patient populations and could shift the treatment paradigm for cardiovascular disease from chronic care to one-and-done treatment," Ruth Gimeno, Lilly group vice president of diabetes and metabolic research and development, said in a statement.

Larger and longer clinical trials will be needed before VERVE-102 can earn approval and reach more patients.