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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 Med­i­cine, 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.

In a pa­per pub­lished last De­cem­ber in Na­ture Biotech­nol­o­gy, Liu’s lab de­scribed 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. (A month be­fore the Liu lab’s work was pub­lished in Na­ture Biotech­nol­o­gy, both teams had re­leased pre-prints of their work with­in a day of each oth­er.)

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 — prime edit­ing has 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.

Ed­i­tors note: This sto­ry was cor­rect­ed to re­move a ref­er­ence to the time­line of re­search by Liu’s team, and a line was added to clar­i­fy the tim­ing of when preprints from each team were pub­lished.

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