Knocking out cholesterol

Consider this scenario, depicted in Nature a few years ago. “It’s 2037, and a middle-aged person can walk into a health centre to get a vaccination against cardiovascular disease. The injection targets cells in the liver, tweaking a gene that is involved in regulating cholesterol in the blood. The simple procedure trims cholesterol levels and dramatically reduces the person’s risk of a heart attack”.

A one-off shot reducing the risk of cardiovascular disease is far in the future. Still, it seems less sci-fi after the macaque monkey trial presented by Verve Therapeutics at the International Society for Stem Cell Research’s annual meeting.

STAT News reports that “when CRISPR base editing was used to knock out two cholesterol-associated genes in monkeys, the animals’ blood levels of heart-disease-causing LDL (“bad”) cholesterol and triglycerides plunged as much as 60% and 65%.” See also the article by Gina Kolata for the New York Times.

The base editor was enclosed in lipid nanoparticles and delivered to the liver, where the genes PCSK9 and ANGPTL3 are expressed. The idea is to confer the protection that a minority of people have naturally, thanks to the inactivation of one of those genes.

Of course, these are preliminary, not yet peer-reviewed results. Verve’s data cover just two weeks of follow-up, and it will be years before human trials can begin. However, this proof-of concept is noteworthy for a couple of reasons.

First, it represents the first successful application of a non-cutting CRISPR system in non-human primates, according to Sekar Kathiresan, co-founder and CEO of the company. Second, gene editing usually targets rare disorders whereas cardiovascular disease is a leading cause of death worldwide (see global trends in cholesterol in this Nature paper).

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