Crispr for the Masses Gets a Little Closer to Reality

A patient in New Zealand last week became the first person to be injected with a drug that is designed to powerfully and permanently lower cholesterol, ushering in a critical test of Crispr gene-editing technology.

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If the drug from Verve Therapeutics works — and that’s still a big open question — it could someday be offered as a one-time shot to address the No. 1 killer in the US: heart disease.

That Crispr is already moving out of the realm of rare diseases and into a common one is a significant development. This trial also comes when new types of gene editors are proliferating, and it could help tip the scales toward some over others.

To bring Crispr to the masses, Verve turned to a newer variation of Crispr called “base editing.” Whereas the original gene-editing tool, Crispr-Cas9, uses a two-part system — “guide RNA” ferries an enzyme called Cas9 to a selected stretch of DNA, which the Cas9 snips out — base editing uses guide RNA alongside a different enzyme capable of changing individual DNA building blocks, or nucleotides.

Such precise, single-letter swaps could be used to fix DNA in people with rare genetic diseases caused by just one wrong letter — an A (adenosine) that should be a G (guanosine), for instance, or a C (cytosine) that should be a T (thymine).

That type of subtle change, if made in just the right spot, could also be used to stop cells from churning out a troublesome protein. That’s Verve’s approach. The company’s one-time injection changes a single letter of DNA in the instructions for building a protein called PCSK9, which is known to drive up levels of LDL, or “bad” cholesterol.

Verve plans to aim the drug at the roughly 1 million people in the US with an inherited form of dangerously high cholesterol called familial hypercholesterolemia. Long term, however, the company thinks its therapy could offer a permanent, potentially more effective alternative to the statins that millions of Americans take every day. In that distant and still theoretical future, the average person could get Verve’s one-time shot to keep cholesterol low enough to avoid heart attacks altogether.

When developing the therapy, Verve assumed it would use the original Crispr gene editor. But after spending six months in the lab comparing Crispr, base editing and several other next-generation editors, base editing won out, in large part because of its precision. Verve licensed the technology from Beam Therapeutics, which was founded in 2017 based on discoveries made by Broad Institute scientist David Liu.

A second reason for using base editors was safety, Verve’s Chief Scientific Officer Andrew Bellinger told me. Base editors modify the genetic code without making breaks in DNA. Scientists have worried the kind of double-stranded breaks made by Crispr-Cas9 could introduce a range of permanent errors if the DNA didn’t paste itself back together correctly. The risk of such errors is especially worrisome when chasing a disease that affects millions of people.

Base editors, for their part, could introduce a different kind of error, in which random single-letter changes are made to DNA, academic research suggests. But Verve is convinced that’s more of a theoretical risk than a real one. At the Food and Drug Administration’s behest, the company has already done extensive experiments to evaluate the risk, Bellinger said.

So far, the approach has worked remarkably well in monkeys. Now, the company will be the first to find out whether the promise of those single-letter edits carries over into humans. The trial is starting in New Zealand with 40 subjects, but Verve hopes to eventually receive permission to enroll people in the UK and the US.

When the initial swath of data from the study comes out next year, scientists and investors alike will go through it with a fine-tooth comb to understand three critical questions: How well does it work to lower cholesterol? Does cholesterol stay low forever? Are there any unexpected safety concerns?

The answers matter not only for Verve but for the millions of people who struggle to keep their cholesterol in check despite the many available drugs on the market.

But they also have broad consequences for the field. The outcome of the study could sway companies like Verve — biotech or big pharma firms that are technology agnostic and simply want to develop the best drug for a particular disease — toward a particular type of gene editor when developing future therapies. It will also raise the question of what other common diseases can be feasibly tackled with current gene-editing approaches. Another nascent effort is using Crispr to engineer stem cells that can be given to people with Type 1 diabetes to try to restore insulin production.

If Verve’s drug works, it will also raise a host of other not insignificant commercial issues, such as whether a one-and-done therapy can ever be made affordable for the masses and whether consumers will be willing to give up their statin pills for a drug that tinkers with their genes.

That gene editing is already having to navigate this thicket of scientific, commercial and ethical questions is nothing short of astonishing. Base editors were discovered in 2016 and 2017. The original Crispr only just turned 10.

As I’ve written before, many technical challenges still need to be overcome for Crispr to go after most other common diseases. But the possibility, however theoretical, that it could make a dent in even this one, heart disease, makes the trial worth watching closely.