Next up for CRISPR: Gene editing for the masses?

CRISPR for high cholesterol is one of MIT Technology Review's 10 Breakthrough Technologies of 2023. Explore the rest of the list here.

We know the basics of healthy living by now. A balanced diet, regular exercise, and stress reduction can help us avoid heart disease-the world's biggest killer. But what if you could take a vaccine, too? And not a typical vaccine-one shot that would alter your DNA to provide lifelong protection?

That vision is not far off, researchers say. Advances in gene editing, and CRISPR technology in particular, may soon make it possible. In the early days, CRISPR was used to simply make cuts in DNA. Today, it's being tested as a way to change existing genetic code, even by inserting all-new chunks of DNA or possibly entire genes into someone's genome.

These new techniques mean CRISPR could potentially help treat many more conditions-not all of them genetic. In July 2022, for example, Verve Therapeutics launched a trial of a CRISPR-based therapy that alters genetic code to permanently lower cholesterol levels.

The first recipient-a volunteer in New Zealand-has an inherited risk for high cholesterol and already has heart disease. But Kiran Musunuru, cofounder and senior scientific advisor at Verve, thinks that the approach could help almost anyone.

The treatment works by permanently switching off a gene that codes for a protein called PCSK9, which seems to play a role in maintaining cholesterol levels in the blood.

Even if you start with a normal cholesterol level, and you turn off PCSK9 and bring cholesterol levels even lower, that reduces the risk of having a heart attack," says Musunuru. It's a general strategy that would work for anyone in the population."

CRISPR's evolution

While newer innovations are still being explored in lab dishes and research animals, CRISPR treatments have already entered human trials. It's a staggering accomplishment when you consider that the technology was first used to edit the genomes of cells about 10 years ago. It's been a pretty quick journey to the clinic," says Alexis Komor at the University of California, San Diego, who developed some of these newer forms of CRISPR gene editing.

Gene-editing treatments work by directly altering the DNA in a genome. The first generation of CRISPR technology essentially makes cuts in the DNA. Cells repair these cuts, and this process usually stops a harmful genetic mutation from having an effect.

Newer forms of CRISPR work in slightly different ways. Take base editing, which some describe as CRISPR 2.0." This technique targets the core building blocks of DNA, which are called bases.

There are four DNA bases: A, T, C, and G. Instead of cutting the DNA, CRISPR 2.0 machinery can convert one base letter into another. Base editing can swap a C for a T, or an A for a G. It's no longer acting like scissors, but more like a pencil and eraser," says Musunuru.

In theory, base editing should be safer than the original form of CRISPR gene editing. Because the DNA is not being cut, there's less chance that you'll accidentally excise an important gene, or that the DNA will come back together in the wrong way.

Verve's cholesterol-lowering treatment uses base editing, as do several other experimental therapies. A company called Beam Therapeutics, for example, is using the approach to create potential treatments for sickle-cell disease and other disorders.

And then there's prime editing, or CRISPR 3.0." This technique allows scientists to replace bits of DNA or insert new chunks of genetic code. It has only been around for a few years and is still being explored in lab animals. But its potential is huge.

That's because prime editing vastly expands the options. CRISPR 1.0" and base editing are somewhat limited-you can only use them in situations where cutting DNA or changing a single letter would be useful. Prime editing could allow scientists to insert entirely new genes into a person's genome.

That would open up many more genetic disorders as potential targets. If you want to correct a specific mutation that is beyond the reach of base editing, prime editing is your only option," says Musunuru.

If it works, it could be revolutionary. A hundred people with a disorder might have all kinds of genetic influences that made them vulnerable to it. But inserting a corrective gene could potentially cure all of them, says Musunuru. If you can put in a fresh new working copy of the gene, it may not matter what mutation you have," he says. You're putting in a working copy, and that's good enough."

Together, these new forms of CRISPR could dramatically broaden the scope of gene-editing treatments-making them potentially available to many more people, and for a much broader range of disorders. The target diseases don't even have to be caused by genetic mutations. In fact, even some of the older CRISPR approaches could be used to target diseases that aren't necessarily the result of a rogue gene. Verve's treatment to permanently lower cholesterol is a first example of a CRISPR treatment that could benefit the majority of adults, according to Musnuru.

Genetic vaccinations

Verve's approach involves swapping a base letter in the gene that codes for the PCSK9 protein. This disables the gene, so much less protein is made. Because the PCSK9 protein plays an important role in maintaining levels of LDL cholesterol-the type associated with clogged arteries-cholesterol levels drop too.

In experiments, when mice and monkeys were given the treatment, their blood cholesterol levels dropped by around 60 to 70% within a few days, says Musunuru. And once it's down, it stays down," he adds. The company expects its first human clinical trial to run for a few years. If the trial is successful, the company will continue with larger trials. The treatment will have to be approved by the US Food and Drug Administration before it can be prescribed by doctors in the US. It will be a while before any [CRISPR treatments] are actually approved for use," says Musunuru.

But in the future, he says, we might be able to use the same approach to protect people from high blood pressure and diabetes.

Komor of UC San Diego says a CRISPR-based treatment to prevent Alzheimer's might also be desirable. But she cautions that editing the genomes of healthy people is ethically ambiguous and could be an unnecessary gamble for people who are otherwise well. If I was given the opportunity to do editing of my liver cells to reduce cholesterol potentially in the future, I would probably say no," she says. I want to keep my genome as is, unless there's a problem."

Any new treatment has to be at least as safe as what is already available, says Tania Bubela, who studies the legal and ethical implications of new technologies at Simon Fraser University in Burnaby, British Columbia. Plenty of drugs have side effects. The difference is that with a drug, you can ... change the person's medication," says Bubela. With a gene therapy, I can't see how you would do that."

The price, as well as the safety, of any gene-editing treatment will determine whether it can really help the masses, Bubela says: I find it difficult to believe that a gene-based therapy like CRISPR will ever be either safer or more cost-effective than a very simple cholesterol pill." But she accepts that these treatments could become cheaper, and that the one-shot" approach might appeal to some.

There's a good reason the first trials of CRISPR have focused on people with rare disorders who have few options, says Komor: Those are the people most in need." While broadening the applications of CRISPR is exciting, she says, we have an ethical obligation to help those people before we help the general masses."