A new gene editing technique dramatically lowers cholesterol in adult monkeys

New step towards a future in which some chronic diseases will be cured forever at the push of a genetic button.

A team of scientists from the American company Verve Therapeutics has inactivated a gene associated with high levels of bad cholesterol in adult monkeys, achieving a reduction of 60%.

The researchers have used - for the first time in primates - the base editors, a sophisticated variant of the CRISPR gene editing tools, winners of the last Nobel Prize in Chemistry.

The authors already speak of “once and done” treatments.

A human's instruction book, written in each of his cells, can be spelled. There are 6,400 million chemical letters (attgctgaa…). A small stretch of this very long molecule, the PCSK9 gene, contains the guidelines for making the PCSK9 protein, which is involved in the bad cholesterol (LDL) destruction system in the liver. When there is a lot of protein, the concentration of LDL increases and fats accumulate in the arteries, which can cause a heart attack. In some population groups, up to 3% of people have natural mutations that inhibit this gene. This genetic characteristic means that they live with lower levels of bad cholesterol and with a lower risk of cardiovascular diseases, the main cause of death in the world.

The Verve Therapeutics team has used the base editors to mimic these natural mutations and inactivate the PCSK9 gene only in the liver cells of nine macaques.

The effects seem permanent: bad cholesterol levels were still low eight months after the intervention, according to the results published this Wednesday in the journal

Nature

.

"The results open the door to a possible therapeutic use of base editors in many metabolic diseases", says the geneticist Lluís Montoliu

The geneticist Lluís Montoliu, from the National Center for Biotechnology, in Madrid, applauds the new study. "The results are surprising and encouraging and open the door to a possible therapeutic use of base editors in many metabolic diseases," says the researcher. Montoliu recalls that the US National Academy of Sciences and other institutions recommended last year to focus on mimicking natural human mutations, to avoid genetic changes with unknown consequences. "Here a gene is mutated that, in fact, is already mutated in many people and this does not seem to negatively affect the health of the monkeys, but quite the opposite," argues the researcher, president of the Association for Responsible Research and Innovation in Genetic Editing, based in Paris.

The main author of the new work is the geneticist and cardiologist Sekar Kathiresan, co-founder of Verve Therapeutics, a company that has raised this year 77 million euros in a round of financing to develop its products. Kathiresan previewed her results with monkeys at a scientific conference a year ago. "Our goal is to develop drugs that, administered once in a lifetime, precisely edit specific genes in the liver to permanently lower LDL cholesterol and triglyceride levels in adults with coronary heart disease," Kathiresan, former director of the Massachusetts General Hospital Center for Genomic Medicine.

Cardiologist José Luis López-Sendón, from La Paz hospital in Madrid, recalls that for five years there have been medications, such as alirocumab and evolocumab, that inhibit the PCSK9 protein and achieve a reduction in bad cholesterol, without genetic changes.

The problem is that they require two injections a month and cost about 700 euros per month, so their use is very restricted.

López-Sendón celebrates the success of the PCSK9 gene editing in monkeys.

“Human studies are lacking, but it is certainly a remarkable scientific advance.

For the reduction of cholesterol but, above all, because it opens a door to modify other genes in other diseases ”, he points out.

"What remains to be seen is the price, which will be crazy," warns the Spanish cardiologist.

"What remains to be seen is the price, which will be crazy," warns cardiologist José Luis López-Sendón

Verve Therapeutics boasts that its technique matches or exceeds the results of drugs currently used to lower bad cholesterol, including statins, which often require a daily dose. "Unlike these drugs, gene editing strategies offer the potential of a single therapy for the definitive treatment of disease," say Kathiresan and her colleagues. One of the main investors in Verve Therapeutics is the company GV, the former Google Ventures, born as a Google venture capital fund.

The CRISPR tools, a kind of molecular scissors, are based on microbe mechanisms discovered by the team of Spanish scientist Francis Mojica about two decades ago. In 2012, French biochemist Emmanuelle Charpentier and American chemist Jennifer Doudna proposed using such microbial scissors as a universal tool to edit any genome. The two scientists shared the 2020 Nobel Prize in Chemistry.

The CRISPR technique was first used in 2016 in China to try to activate white blood cells in the laboratory and make them more potent against a type of lung cancer. In 2018, the US authorized the first

in vivo

, in-patient

trial

. The American company Editas Medicine injected CRISPR tools directly into the eyes of patients with Leber congenital amaurosis, with the aim of correcting a defective mutation in the cells of their retinas.

The problem with the original CRISPR tools, as seen in recent years, is that they cause unwanted mutations. Researchers at Verve Therapeutics have used an improved version, developed by Beam Therapeutics, another American company founded, among others, by scientists Feng Zhang and David Liu, two of the world's leading leaders in modifying the human genome. One of Beam's catchphrases is: "Rewriting the genetic sequence, letter by letter." Its base editor acts as a much more precise typex: it seems capable of erasing one of the 6.4 billion chemical letters and replacing it with another.

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