Lifetime Treatment For High Cholesterol With CRISPR-Based Therapies Achieved A Milestone

Wednesday - November 22 2023, 11:16 UTC - 1 year ago

In a small clinical trial of 10 people genetically prone to dangerously high levels of cholesterol, a single infusion of the precision gene editor reduced artery-clogging fat by up to 55%. This marks the first use of a newer class of gene editors directly in humans. VERVE-101 is a therapy designed to disable a gene encoding a liver protein that regulates cholesterol using base editing with nanoparticles. Although two people experienced severe heart issues, it is a breakthrough that base editing works efficiently in the liver.

CRISPR-based therapies just hit another milestone.

In a small clinical trial with 10 people genetically prone to dangerously high levels of cholesterol, a single infusion of the precision gene editor slashed the artery-clogging fat by up to 55 percent. If all goes well, the one-shot treatment could last a lifetime.

The trial, led by Verve Therapeutics, is the first to explore CRISPR for a chronic disease that’s usually managed with decades of daily pills. It also marks the first use of a newer class of gene editors directly in humans. Called base editing, the technology is more precise—and potentially safer—than the original set of CRISPR tools. The new treatment, VERVE-101, uses a base editor to disable a gene encoding a liver protein that regulates cholesterol.

To be clear, these results are just a sneak peek into the trial, which was designed to test for safety, rather than the treatment’s efficacy. Not all participants responded well. Two people suffered severe heart issues, with one case potentially related to the treatment.

Nevertheless, "it is a breakthrough to have shown in humans that in vivo [in the body] base editing works efficiently in the liver," Dr. Gerald Schwank at the University of Zurich, who wasn’t involved in the trial, told Science.

Give Your Heart a Break .

CRISPR has worked wonders for previously untreatable cancers. Last week, it was also approved in the United Kingdom for the blood diseases sickle cell and beta thalassemia.

For these treatments, scientists extract immune cells or blood cells from the body, edit the cells using CRISPR to correct the genetic mistake, and reinfuse the treated cells into the patient. For edited cells to "take," patients must undergo a grueling treatment to wipe out existing diseased cells in the bone marrow and open space for the edited replacements.

Verve is taking a different approach: Instead of isolating cells for gene editing, the tools are infused into the bloodstream where they edit genes directly inside the body. It’s a big gamble. Most of our cells contain the same DNA. Once injected, the tools could go on a rampage and edit the targeted gene throughout the body, causing dangerous side effects.

Verve tackled this concern head on by pairing base editing with nanoparticles.

The trial targeted PCSK9, a liver protein that keeps low-density lipoprotein (LDL), or "bad cholesterol," levels at bay. In familial hypercholesterolemia, a single mutated letter in PCSK9 alters its function, causing LDL levels to grow dangerously. People with this inherited disorder are at risk of life-threatening heart problems by the age of 50 and need to take statin drugs to keep their cholesterol in check. But the lifelong regime is tough to maintain.

A Targeted CRISPR Torpedo .

Verve designed a "one-and-done" treatment to correct the PCSK9 mutation in these patients.

The therapy employs two key strategies to boost efficacy.

The first is called base editing. The original CRISPR toolset acts like scissors, cutting both strands of DNA, making the edit, and patching the ends back together. The process often leaves room for mistakes, such as the unintended rearranging o f gene segments. Base editing, however, functions more like a pencil, directly rewriting one "letter" in the gene code without the need for cutting and pasting.

The second weapon in Verve's arsenal is nanoparticles. These microscopic particles package the editing tools into a protective coating, allowing them to reach the liver’s cells without interacting with other parts of the body. They ensure that the editing is limited to the intended target.