Image: Shutterstock

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.

Up­dat­ed: FDA re­mains silent on or­phan drug ex­clu­siv­i­ty af­ter last year's court loss

Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

Thomas Gad, Y-mAbs Therapeutics founder and interim CEO

FDA re­jects Y-mAbs’ neu­rob­las­toma drug af­ter tak­ing is­sue with clin­i­cal tri­al de­sign

Uncertainty about clinical trial evidence has led the FDA to hand down a complete response letter for Y-mAbs’ neuroblastoma drug, casting a cloud on the future of a candidate that had gone through a long development journey in a rare pediatric cancer.

Y-mAbs said it’s disappointed “but not surprised” given that the agency’s oncology drug advisory committee had voted 16-0 against its drug’s approval a few weeks ago.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 153,900+ biopharma pros reading Endpoints daily — and it's free.

Philip Tagari switch­es Am­gen's dis­cov­ery lab for in­sitro's ma­chine learn­ing tools; CEO Joaquin Du­a­to to chair J&J's board

In February, Philip Tagari will take a few days of retirement and then immediately return to industry. He won’t be leading the therapeutics discovery unit for a large biopharma, though.

He’ll trade in his Amgen hat for chief scientist at a machine learning startup that has reeled in hundreds of millions in capital to lay the groundwork for a much-hyped new model of drug discovery that aims to speed up the time to new clinical assets.

Raul Rodriguez, Rigel Pharma CEO

Rigel Phar­ma scores FDA ap­proval for leukemia, kick­ing off show­down with Servi­er in IDH1

When Rigel Pharma bought olutasidenib from Forma Therapeutics, it acquired a drug that already secured a PDUFA date at the FDA — for February 2023. But regulators are ready to give their OK sooner than that.

The FDA has approved the IDH1 inhibitor as a treatment for adult patients with relapsed or refractory acute myeloid leukemia who have a susceptible IDH-1 (isocitrate dehydrogenase-1) mutation as detected by an FDA-greenlit test. Rigel will market it as Rezlidhia.

Tim Pearson, Carrick Therapeutics CEO

Pfiz­er backs $60M in­fu­sion in­to Car­rick, teams up on breast can­cer treat­ment

In a big week for Carrick Therapeutics, the company announced $60 million in funding for its lead breast cancer drug and development of a second program, as well as a collaboration with Pfizer for combo development.

The $35 million from Pfizer comes with an agreement under which Pfizer will support Carrick’s Phase II study of samuraciclib in combination with Pfizer’s Faslodex for advanced breast cancer. Along with the investment, Adam Schayowitz, vice president and development head of breast cancer, colorectal cancer and melanoma at Pfizer global product development, will join Carrick’s scientific advisory board.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 153,900+ biopharma pros reading Endpoints daily — and it's free.

Paul Hudson, Sanofi CEO (Romuald Meigneux/Sipa via AP Images)

Sanofi and Am­gen are bring­ing cash to cov­er the ta­ble stakes for the Hori­zon M&A game

With the market cap on Horizon Therapeutics $HZNP pushed up to the $23 billion mark today, one of the Big Pharmas in the hunt for a major league buyout deal signaled it’s playing the M&A game with cash.

Paris-based Sanofi, where CEO Paul Hudson has been largely focused on some risky biotech acquisitions to win some respect for its future pipeline prospects, issued a statement early Friday — complying with Rule 2.12 of the Irish takeover rules — making clear that while the certainty or size of an offer can’t be determined, any offer “will be solely in cash.” And Amgen CEO Robert Bradway came right in behind him, filing a statement on the London Stock Exchange overnight that any offer they may make will “likely” be in cash as well.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 153,900+ biopharma pros reading Endpoints daily — and it's free.

Illustration: Assistant Editor Kathy Wong for Endpoints News

As mon­ey pours in­to dig­i­tal ther­a­peu­tics, in­sur­ance cov­er­age crawls



Talk therapy didn’t help Lily with attention deficit hyperactivity disorder, or ADHD. But a video game did.

As the 10-year-old zooms through icy waters and targets flying creatures on the snow-capped planet Frigidus, she builds attention skills, thanks to Akili Interactive Labs’ video game EndeavorRx. She’s now less anxious and scattered, allowing her to stay on a low dose of ADHD medication, according to her mom Violet Vu.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Eli Lil­ly’s Alzheimer’s drug clears more amy­loid ear­ly than Aduhelm in first-ever head-to-head. Will it mat­ter?

Ahead of the FDA’s decision on Eli Lilly’s Alzheimer’s drug donanemab in February, the Big Pharma is dropping a first cut of data from one of the more interesting trials — but less important in a regulatory sense — at an Alzheimer’s conference in San Francisco.

In the unblinded 148-person study, Eli Lilly pitted its drug against Aduhelm, Biogen’s drug that won FDA approval but lost Medicare coverage outside of clinical trials. Notably, the study didn’t look at clinical outcomes, but rather the clearance of amyloid, a protein whose buildup is associated with Alzheimer’s disease, in the brain.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 153,900+ biopharma pros reading Endpoints daily — and it's free.

Lynn Baxter, Viiv Healthcare's head of North America

Vi­iV dri­ves new cor­po­rate coali­tion in­clud­ing Uber, Tin­der and Wal­mart, aimed at end­ing HIV

ViiV Healthcare is pulling together an eclectic coalition of consumer businesses in a new White House-endorsed effort to end HIV by the end of the decade.

The new US Business Action to End HIV includes pharma and health companies — Gilead Sciences, CVS Health and Walgreens — but extends to a wide range of consumer companies that includes Tinder, Uber and Walmart.

ViiV is the catalyst for the group, plunking down more than half a million dollars in seed money and taking on ringmaster duties for launch today on World AIDS Day, but co-creator Health Action Alliance will organize joint activities going forward. ViiV and the alliance want and expect more companies to not only join the effort, but also pitch in funding.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 153,900+ biopharma pros reading Endpoints daily — and it's free.