MIT researchers reveal DNA “Paste” tech behind latest gene editing startup

MIT scientists have developed a tool that they say can insert large gene sequences where they want in the genome.

Omar Abudayyeh

In a paper published Thursday in Nature Biotechnology, MIT fellows Omar Abudayyeh, Jonathan Gootenberg and colleagues detail a technology they call PASTE, which they say can potentially be used to insert long strands of DNA and treat genetic diseases caused by many different mutations, such as cystic fibrosis and Leber congenital amaurosis, a rare eye disorder that causes blindness.

The technology has been licensed to Tome Biosciences — a biotech co-founded by the duo back in February of 2021 and backed by ARCH, Google’s venture arm, a16z, Longwood Fund, Polaris Partners and Alexandria Venture, which joined after its Series A, according to a recent pitch deck obtained by Endpoints News.

Jonathan Gootenberg

Sana Biotechnology also has a stake in the company, according to an April SEC filing.

Abudayyeh and Gootenberg declined to comment on Tome. The Watertown, MA-based biotech is led by CEO Rahul Kakkar and has more than 80 full-time employees as of the third quarter of this year, according to the pitch deck slides.

In the paper, the researchers explain how they fuse two existing technologies: a prime editor, which the Broad’s David Liu pioneered and spun out into the startup Prime Medicines, and an integrase, an enzyme some viruses use to infect bacteria by inserting their DNA into the host cells.

The idea behind the combined technologies is that integrases on their own aren’t easily engineered to insert at any location besides their specific target sequence, but they’re capable of carrying big sequences. Prime editors, meanwhile, can be engineered to target and edit specific spots, but only in short bits — just enough to stick in a target sequence for the integrase. By combining the two in PASTE, researchers can insert sequences as large as 36,000 base pairs, in the spots that they want.

David Liu

Abudayyeh told Endpoints News that unlike current gene-editing approaches, which can only go after single mutations of a disease at once, PASTE could address many mutations at the same time at once by replacing the whole gene. In addition, the technique doesn’t create a double-stranded break in the DNA, reducing the risk of unwanted insertions or deletions, he said.

The work builds on part of a paper published in Nature last year where Liu’s lab describes a similar approach. The only difference is that Liu’s lab opted not to fuse all the machinery together, having the prime editor and integrase work separately. In their paper, Gootenberg and Abudayyeh report higher efficiency than Liu’s paper did.

Kiran Musunuru

Liu said in an email, “In our lab’s hands the prime editor–recombinase fusion does not on average work better than simply expressing the recombinase as a separate protein, and in some cases, the fusions worked less efficiently than the separately expressed proteins.”

Both Kiran Musunuru, University of Pennsylvania professor and Verve Therapeutics co-founder, and Sam Sternberg, Columbia professor and Prime advisor, said that they thought both were similar. “Is there a big difference? Probably not in the grand scheme of things,” Musunuru said. “I don’t think it matters too much whether it’s two different proteins made separately or whether it’s a single protein. They both seem to work reasonably well.”

Sam Sternberg

Musunuru, who researches the genetics of heart disease, said he’s been using PASTE in his own lab too, after the preprint was published last year, though while his lab has gotten the technology to work in cells, it hasn’t gotten it to work in mice. Verve uses a form of gene editing called base editing, licensed from Liu’s other biotech Beam Therapeutics.

Notably, Tome doesn’t have a license with Prime Medicine, which houses Liu’s prime editing patents from the Broad, and is not in talks for one, a spokesperson for Prime Medicine told Endpoints.

Abudayyeh and Gootenberg emphasized that while they used prime editing in their paper, the more general PASTE framework was not limited to prime editing. “Prime is one example, but not the only way to do it,” Gootenberg said.

Musunuru wasn’t so sure, noting that he didn’t see how you could make the technique programmable, or targetable, “without something very similar to prime editing.”

Getting crispy

Abudayyeh and Gootenberg are alumni of CRISPR pioneer Feng Zhang’s lab. They’ve launched several biotechs, including Sherlock Biosciences and Proof Diagnostics, both diagnostics companies they co-founded with Zhang and others, and Moment Biosciences, a stealth company that is developing “precision microbiome therapy,” according to a Massachusetts corporate filing. And then, of course, there’s Tome.

The industry is paying a lot of attention and money to the next iterations of CRISPR. Prime launched last year with $315 million and raised $175 million when it went public in October. Then there’s Tessera, which in August raised $300 million, putting its total funds raised over the $500 million mark. In February, Intellia, which is using CRISPR to edit genes directly in the body, bought for $45 million cash little-known Rewrite Therapeutics, which its investor called “kind of CRISPR 2.0,” a moniker applied to the likes of base and prime editing, though little else was said of its technology.

Researchers are still in the early days of turning such a technology into a commercial therapy — these ‘CRISPR 2.0’ techniques have never been used in humans. In Abudayyeh and Gootenberg’s paper, they were able to get the DNA they wanted into a mouse’s liver cells less than 3% of the time. Musunuru said that there was a lot of space for improvement, noting that they would have to get to around at least 10% to have some therapeutic effect.

In the pitch deck, Tome says it hopes to be in the clinic by 2026.

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gene editing
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