Edits To a Cholesterol Gene Could Stop the Biggest Killer On Earth

A volunteer in New Zealand has become the first person to undergo DNA editing in order to lower their blood cholesterol, a step that may foreshadow wide use of the technology to prevent heart attacks. MIT Technology Review reports: The experiment, part of a clinical trial by the US biotechnology company Verve Therapeutics, involved injecting a version of the gene-editing tool CRISPR in order to modify a single letter of DNA in the patient's liver cells. According to the company, that tiny edit should be enough to permanently lower a person's levels of "bad" LDL cholesterol, the fatty molecule that causes arteries to clog and harden with time. The patient in New Zealand had an inherited risk for extra-high cholesterol and was already suffering from heart disease. However, the company believes the same technique could eventually be used on millions of people in order to prevent cardiovascular disease. In New Zealand, where Verve's clinical trial is taking place, doctors will give the gene treatment to 40 people who have an inherited form of high cholesterol known as familial hypercholesterolemia, or FH. People with FH can have cholesterol readings twice the average, even as children. Many learn they have a problem only when they get hit with a heart attack, often at a young age. The study also marks an early use of base editing, a novel adaptation of CRISPR that was first developed in 2016. Unlike traditional CRISPR, which cuts a gene, base editing substitutes a single letter of DNA for another. The gene Verve is editing is called PCSK9. It has a big role in maintaining LDL levels and the company says its treatment will turn the gene off by introducing a one-letter misspelling. [...] One reason Verve's base-editing technique is moving fast is that the technology is substantially similar to mRNA vaccines for covid-19. Just like the vaccines, the treatment consists of genetic instructions wrapped in a nanoparticle, which ferries everything into a cell. While the vaccine instructs cells to make a component of the SARS-CoV-2 virus, the particles in Verve's treatment carry RNA directions for a cell to assemble and aim a base-editing protein, which then modifies that cell's copy of PCSK9, introducing the tiny mistake. In experiments on monkeys, Verve found that the treatment lowered bad cholesterol by 60%. The effect has lasted more than a year in the animals and could well be permanent. The report notes that the human experiment does carry some risk. "Nanoparticles are somewhat toxic, and there have been reports of side effects, like muscle pain, in people taking other drugs to lower PCSK9," reports MIT Technology Review. "And whereas treatment with ordinary drugs can be discontinued if problems come up, there's as yet no plan to undo gene editing once it's performed."

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