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Biotechnology and health

Edits to a cholesterol gene could stop the biggest killer on earth

In a first, a patient in New Zealand has undergone gene-editing to lower their cholesterol. It could be the beginning of new era in disease prevention.

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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.

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.

“If this works and is safe, this is the answer to heart attack—this is the cure,” says Sekar Kathiresan, a gene researcher who started Verve three years ago and is the company’s CEO.

It’s been 10 years since scientists developed CRISPR, a technology for making targeted changes to the DNA in cells, but until now the method has been tried only on people suffering from rare diseases like sickle-cell anemia, and only as part of exploratory trials.

Sek Kathiresan, the CEO of Verve
Sekar Kathiresan, a cardiologist and genetics researcher, is the CEO of Verve

If Verve’s experiment works, it could signal far wider use of gene editing to prevent common conditions. Large swaths of the world’s population have LDL that is too high, but many people can’t get it under control. Worldwide, more people die of atherosclerotic cardiovascular disease than from anything else.

 “Of all the different genome editing ongoing on the clinic, this one could have the most profound impact because of the number of people who could benefit,” says Eric Topol, a cardiologist and researcher at Scripps Research.

Some doctors believe lowering LDL aggressively, and keeping it low throughout life, could essentially prevent people from dying of cardiovascular disease. That is the view of Eugene Braunwald, a physician at Brigham & Women’s Hospital in Boston who is also an advisor to Verve.

“The lower the LDL, the better,” says Braunwald. “You can’t have too low an LDL. The problem is how do you get it down?”

A strict diet, like one where you avoid eggs, meat, and even olive oil, can help. But few people succeed in sticking to it. Then come statins, the most widely prescribed medicine in the US. These pills can cut a person’s LDL in half, but some can’t handle the side effects, and some find even taking a once-a-day pill hard to manage.

Some newer biotech drugs involve injections twice a month, or even just twice a year. These drugs are quite powerful, and Braunwald recently speculated what would occur if they were given widely as a public health intervention, not unlike an annual flu vaccine. “I calculate it if you give it starting at age 30, you will live to 100 without coronary artery disease,” he says.

However, those drugs aren’t yet widely used. They remain costly, are still inconvenient, and insurers balk at paying. “So gene editing is the big stick, because it’s one and done. You don't ever have to come back,” says Braunwald. “It’s a very big deal, because atherosclerotic cardiovascular disease is the most common cause of death in the industrialized world, and LDL is the primary reason.”

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.

Before starting Verve, Kathiresan was a geneticist working at the Broad Institute in Cambridge, Massachusetts, looking for inherited causes of heart disease. He started Verve after his brother, Senthil, was struck down suddenly by a heart attack; base editing, he thought, could be a way to prevent such tragedies.

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 human experiment could entail 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. 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.

So far, the few gene therapies on the market all cost hundreds of thousands of dollars—even as much as $2 million. But Verve’s should be much cheaper, especially if used widely. One reason is that whereas other gene therapies use specially prepared viruses to carry genes, nanoparticles are made in a chemical process that’s more practical to scale up.

“The pandemic and the emergent need for vaccines [created] large-scale manufacturing capacity,” says Kiran Musunuru, a gene-editing expert at the University of Pennsylvania who cofounded Verve.  That capacity “can be easily repurposed for genetic therapy,” he says, and “of course, abundant capacity means reduced prices.”

Musunuru says people are even thinking about “booster shots” in case the first round of gene editing isn’t complete, or in order to knock out other cholesterol genes and deepen the effect on LDL.

It’s a stroke of luck for Verve’s founders that the main cause of death in the world is also the first common problem that gene editing can address. Kathiresan, who takes a statin to keep his LDL low, says he thinks gene editing for cholesterol has the potential to be a life-extension treatment.

“The number one cause of mortality in the world is heart attack,” he says. "If you are going to give a medicine that makes you avoid a heart attack, people are going to live longer.”

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