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Base editing, a new form of gene therapy, sharply lowers bad cholesterol in clinical trial

Twist on CRISPR could with one treatment help prevent heart disease, a major killer, in many people.

A technique for precisely rewriting the genetic code directly in the body has slashed “bad” cholesterol levels—possibly for life—in three people prone to dangerously high levels of the artery-clogging fat. The feat relied on a blood infusion of a so-called base editor, designed to disable a liver protein, PCSK9, that regulates cholesterol.

“It is a breakthrough to have shown in humans that in vivo base editing works efficiently in the liver,” says Gerald Schwank, a gene-editing researcher at the University of Zurich who wasn’t involved in the clinical trial, sponsored by the biotech Verve Therapeutics. The approach is more precise, and possibly safer, than disrupting a gene with CRISPR, the gene-editing tool from which base editing is derived.

Reported today at the American Heart Association meeting in Philadelphia, the results mark the first time this CRISPR variant has been infused into people to treat a disease. The success is also a proof of principle for using gene editing for a common health problem like high cholesterol rather than a rare disease. Verve hopes its base editor could eventually be a one-time solution for tens of millions of middle-aged people who are struggling to control their cholesterol with daily drugs.

Some clinicians worry, however, that the treatment’s cost could be exorbitant—some approved gene therapies are priced in the millions—and prevent it from reaching many who could be helped. And the short- and long-term safety of base editing remains unclear. Two of the trial’s 10 participants, nearly all born with various gene mutations resulting in high cholesterol levels, had a heart attack or cardiac arrest, in one case possibly related to the treatment. “It worked. But we won’t know for years how safe this is,” says cardiologist Karol Watson of the University of California, Los Angeles.

Traditional gene therapy, which shuttles a therapeutic gene into the body, is becoming more common. CRISPR, too, has chalked up clinical victories. U.S. regulators are poised to approve the gene editor for the blood disorder sickle cell disease, and in small studies, an infusion of CRISPR has been used to shut off a liver protein to treat two genetic diseases.

But CRISPR works by severing both strands of DNA and letting cells themselves imperfectly repair the break. This can result in potentially harmful DNA rearrangements that could flip on a cancer gene. Base editors, a twist on CRISPR invented in 2016 by David Liu’s lab at Harvard University and the Broad Institute, are more precise because they nick just one DNA strand and swap out pairs of the four DNA bases.

Originally published at

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