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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.

Has the mo­ment fi­nal­ly ar­rived for val­ue-based health­care?

RBC Capital Markets’ Healthcare Technology Analyst, Sean Dodge, spotlights a new breed of tech-enabled providers who are rapidly transforming the way clinicians deliver healthcare, and explores the key question: can this accelerating revolution overturn the US healthcare system?

Key points

Tech-enabled healthcare providers are poised to help the US transition to value, not volume, as the basis for reward.
The move to value-based care has policy momentum, but is risky and complex for clinicians.
Outsourced tech specialists are emerging to provide the required expertise, while healthcare and tech are also converging through M&A.
Value-based care remains in its early stages, but the transition is accelerating and represents a huge addressable market.

Lat­est on ul­tra-rare dis­ease ap­proval; Pos­i­tive, if mixed, signs for Bio­gen's ALS drug; Clay Sie­gall finds a new job; and more

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FDA spells out how can­cer drug de­vel­op­ers can use one tri­al for both ac­cel­er­at­ed and full ap­provals

The FDA’s Oncology Center of Excellence has been a bright spot within the agency in terms of speeding new treatments to patients. That flexibility was on full display this morning as FDA released new draft guidance spelling out exactly how oncology drug developers can fulfill both the accelerated and full approval’s requirements with just a single randomized controlled trial.

While Congress recently passed legislation that will allow FDA to require confirmatory trials to be recruiting and ongoing prior to granting an accelerated approval, the agency is now making clear that the initial trial used to win the AA, if designed appropriately, can also serve as the trial for converting the accelerated approval into a full approval.

Clay Siegall, Morphimmune CEO

Up­dat­ed: Ex-Seagen chief Clay Sie­gall emerges as CEO of pri­vate biotech

Clay Siegall will be back in the CEO seat, taking the helm of a private startup working on targeted cancer therapies.

It’s been almost a year since Siegall resigned from Seagen, the biotech he co-founded and led for more than 20 years, in the wake of domestic violence allegations by his then-wife. His eventual successor, David Epstein, sold the company to Pfizer in a $43 billion deal unveiled last week.

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FDA ad­vi­sors unan­i­mous­ly rec­om­mend ac­cel­er­at­ed ap­proval for Bio­gen's ALS drug

A panel of outside advisors to the FDA unanimously recommended that the agency grant accelerated approval to Biogen’s ALS drug tofersen despite the drug failing the primary goal of its Phase III study, an endorsement that could pave a path forward for the treatment.

By a 9-0 vote, members of the Peripheral and Central Nervous System Drugs Advisory Committee said there was sufficient evidence that tofersen’s effect on a certain protein associated with ALS is reasonably likely to predict a benefit for patients. But panelists stopped short of advocating for a full approval, voting 3-5 against (with one abstention) and largely citing the failed pivotal study.

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No­vo Nordisk oral semaglu­tide tri­al shows re­duc­tion in blood sug­ar, plus weight loss

Novo Nordisk is testing higher levels of its oral version of its GLP-1, semaglutide, and its type 2 diabetes trial results released today show reductions in blood sugar as well as weight loss.

In the Phase IIIb trial, Novo compared its oral semaglutide in 25 mg and 50 mg doses with the 14 mg version that’s currently the maximum approved dose. The trial looked at how the doses compared when added to a stable dose of one to three oral antidiabetic medicines in people with type 2 diabetes who were in need of an intensified treatment.

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Sijmen de Vries, Pharming CEO

FDA ap­proves Pharm­ing drug for ul­tra-rare im­mun­od­e­fi­cien­cy dis­ease

US regulators cleared an ultra-rare drug from Pharming Group, by way of Novartis, on Friday afternoon.

The Dutch biotech said the FDA greenlit leniolisib for an immunodeficiency disease known as activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome, or APDS. People 12 years and older can receive the oral drug, to be marketed as Joenja, beginning early next month, Pharming said, five days ahead of the decision deadline set by the FDA as part of a priority review.

Eu­ro­pean doc­tors di­al up dig­i­tal com­mu­ni­ca­tion with phar­mas, but still lean to­ward in-per­son med meet­ings, study finds

As in-person sales rep access declines in the big five European countries, a corresponding uptick in virtual rep access is happening. It’s not surprising, but it does run counter to pharma companies’ assessment – along with long-held sales rep sway in Europe – that in-person access hadn’t changed.

CMI Media Group and Medscape’s recent study reports that 75% of physicians in the EU5 countries of Spain, Germany, Italy, France and the UK already limit engagements with pharma sales reps, and 25% of those surveyed plan to decrease time with reps.

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Judge al­lows ex­pert tes­ti­mo­ny in GSK tri­al al­leg­ing Zan­tac link to can­cer

A California judge will allow a plaintiff in a state court case to introduce expert testimony connecting a potential carcinogen in former blockbuster medicine Zantac to cancer.

The order was handed down on Thursday from state judge Evelio Grillo, who is now allowing both parties to introduce expert testimony in an upcoming trial after what’s known as a Sargon hearing, where a judge determines the admissibility of expert witnesses and expert opinions.