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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.

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.

Big week for Alzheimer’s da­ta; As­traZeneca buys cell ther­a­py start­up; Dig­i­tal ther­a­peu­tics hits a pay­er wall; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

You may start to notice more stories exclusively available to Premium subscribers. This week alone, paid subscribers can read our in-depth reporting on Alzheimer’s data, digital therapeutics and Allogene’s cell therapy for solid tumors, as well as scoops on Twitter ads and Catalent. With your support, we can keep growing our team and spend more time on quality work. We have both individual and company plans available — check them out to unlock the full Endpoints experience.

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Am­gen, years be­hind ri­vals, says PhI obe­si­ty drug shows dura­bil­i­ty signs

While NBC ran “The Biggest Loser” for 17 seasons, deemed toxic by critics for the reality show’s punishing exercise and diet upheavals, researchers in pharmaceutical labs have been attempting to create prescription drugs that induce weight loss — and one pharma betting it can require less frequent dosing is out with a new crop of data.

Amgen was relatively late to the game compared to its approved competitor Novo Nordisk and green light-approaching rival Eli Lilly. But early data suggested Amgen’s AMG 133 led to a 14.5% weight reduction in the first few months of dosing, buoying shares earlier this fall, and now the California pharma is out with its first batch of durability data showing that figure fell slightly to 11.2% about 150 days after the last dose. Amgen presented at the 20th World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease on Saturday afternoon.

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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.

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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.

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US month­ly costs for biosim­i­lars 'sub­stan­tial­ly high­er' than Ger­many or Switzer­land, JA­MA re­search finds

As the global biologics market is expected to hit nearly the half-trillion-dollar mark this year, new JAMA research points to the importance of timely biosimilar entry, particularly as fewer biosimilars are entering the US than in Europe, and as monthly treatment costs for biosimilars were “substantially higher” in the US compared with Germany and Switzerland.

Among the three countries, biosimilar market share at launch was highest in Germany, but increased at the fastest rate in the US, the authors from the University of Zurich’s Institute of Law wrote in JAMA Network Open today.

Kirk Myers is shown in a still image from a new film series showcasing the efforts of HIV advocates funded by Gilead.

Gilead spot­lights HIV projects and the com­mu­ni­ty lead­ers dri­ving them in new mi­ni-doc­u­men­tary films

Gilead is going behind the scenes of some of the HIV initiatives it funds through grants in a new film series narrated by the people helming the projects.

The first four films and leaders come from across the US — Arianna Lint in Florida and Puerto Rico, Cleve Jones in San Francisco, June Gipson in Mississippi and Kirk Myers in Texas. Their HIV-focused efforts range from addressing unmet needs of the transgender community to delivering social services and high-quality health care in underserved communities.

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EMA pulls an opi­oid from the 1950s used to treat dry cough

The European Medicines Agency said Friday that it’s pulling from all European markets pholcodine-containing medicines, which are an opioid used in adults and children for the treatment of dry cough and in combo with other drugs as a treatment for cold and flu.

The decision to pull the medicines comes as the EMA points to the results from the recent ALPHO study, which show that use of pholcodine during the 12 months preceding anesthesia is linked to a risk of an anaphylactic reaction related to the neuromuscular blocking agents (NMBAs) used (with an adjusted OR of 4.2, and a 95% confidence interval of 2.5 to 6.9).

John Evans, Beam Therapeutics CEO

Beam's base-edit­ed al­lo­gene­ic CAR-T gets FDA go-ahead af­ter four-month wait

The FDA wanted more information on four key areas before it would let Beam Therapeutics proceed with human testing for a cell therapy in a certain type of leukemia. It appears the biotech has answered the agency’s queries.

The US regulator cleared the base-edited, off-the-shelf CAR-T, Beam said Friday morning, lifting a hold from this summer. More details on specific next steps for the Phase I will come out next year, the Boston-area biotech said.

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