Drugs based on next-generation gene editing are moving toward the clinic faster than CRISPR 1.0

Later this year, the now-Nobel prize-winning paper authored by Jennifer Doudna and Emmanuelle Charpentier — in which they described how a primordial immune system in bacteria could be harnessed to edit the genomes of other organisms — will turn 10 years old. The discovery that CRISPR could be turned into an easily programmable tool for rewriting DNA launched biomedical research into warp drive.

In the 10 years leading up to 2012, 200 papers mentioned CRISPR. In 2020 alone, there were more than 6,000. The last decade has seen scientists use CRISPR to cure mice of progeria, fix muscular dystrophy in dogs, and eliminate symptoms for people with genetic blood disorders. Currently, there are more than two dozen human trials of the technology underway around the world.

STAT has created a new tracker of milestone CRISPR studies, and found that the explosion in interest created a positive feedback loop, accelerating the movement of new and better gene editing approaches toward the clinic. For CRISPR 1.0 therapies — those using the original Cas9 cutting enzyme described in the Doudna paper — four-and-a-half years passed, on average, between the first studies in cells and the first public data in non-human primates. Base editing, or CRISPR 2.0, got it down to three years, according to the CRISPR TRACKR.

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This time-shaving trend is evident in other ways, too. Last November, Beam Therapeutics announced it had gotten the green light to test its base editing technology in humans for treating sickle cell disease. If it begins dosing patients this year, that will put Beam just a few years behind the CRISPR 1.0 companies — Intellia, Editas Medicine, and Crispr Therapeutics — which began clinical studies of therapies for various genetic disorders in 2021, 2020, and 2019, respectively, effectively shortening the development time from an average of eight years to six.

“We’re now seeing a real acceleration in progress,” said Kiran Musunuru, a gene editing researcher at the University of Pennsylvania and the co-founder of Verve Therapeutics. “As the challenges are worked out for version 1.0, it just makes it much much easier to substitute in version 2.0 and then 3.0 and then whatever is next.”

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The first five years after Doudna and Charpentier’s (and Feng Zhang’s and George Church’s) seminal papers were published, the field was consumed with fine-tuning how CRISPR-Cas9 worked in different kinds of cells, setting records for how many cuts it could make, and finding medically relevant applications for its targeted gene-breaking abilities.

The next five, driven by a gold rush in finding, engineering, or evolving new CRISPR proteins, saw the gene editing toolbox expand rapidly outward. These newer, shinier, crisper versions of CRISPR pushed forward faster toward the clinic, propelled by all the groundwork that had been laid by its older, clunkier cousin.

“The thing that’s frankly exhilarating to me, as a gray-haired veteran of editing, is how rich the overall ecosystem has become,” said Fyodor Urnov, scientific director of the Innovative Genomics Institute at the University of California, Berkeley, which is headed by Doudna.

Urnov compared the 2000s, when he and others were working on pre-CRISPR versions of genome editing, to medieval times, with a few labs toiling away in their fiefdoms, separated by large tracts of no-man’s land. The tools were few, and difficult to come by. Today, Urnov said, dialing up a gene editing experiment is more like clicking open the app store on your smartphone. Not only will you find options for different kinds of editors and modes for delivering them, but each comes with ratings and reviews too.

“Ten years ago, the ability to just walk into this enormous smorgasbord of offerings simply didn’t exist,” he said.

For many of these tools, it’s still too early to say which ones will take off into components of blockbuster therapies and which ones will burn out upon takeoff. But with the field moving at warp speed, it won’t be long before we know.

Source: STAT