Omar Abudayyeh (R) and Jon Gootenberg

Two Feng Zhang lab alum­ni find a new CRISPR en­zyme that could take a Big Gulp out of RNA — and a raft of dev­as­tat­ing dis­eases

MIT bud­dy bi­ol­o­gists Omar Abu­dayyeh and Jon Gooten­berg were sit­ting in the Que­bec Con­ven­tion Cen­ter at the an­nu­al CRISPR con­fer­ence in 2019 when, buried in a pre­sen­ta­tion on bac­te­r­i­al evo­lu­tion, they heard a nugget that made them chase down the pre­sen­ters the mo­ment they walked off stage.

Abu­dayyeh and Gooten­berg had worked to­geth­er since they were grad­u­ate stu­dents at CRISPR pi­o­neer Feng Zhang’s lab, where they dis­cov­ered a new gene edit­ing en­zyme called Cas13. Un­like most pre­vi­ous Cas en­zymes, Cas13 cut RNA in­stead of DNA. So the pair thought it might pro­vide a po­tent tool for treat­ing dis­eases, such as Hunt­ing­ton’s dis­ease or mus­cu­lar dy­s­tro­phy, caused by mistyped RNA.

Cas13, though, works by a strange and fe­ro­cious mech­a­nism; once it latch­es on­to a pre­cise shred, it goes ham and shreds ge­net­ic ma­te­r­i­al left and right. In hu­mans, the re­sults would be dis­as­trous.

“It ac­tu­al­ly starts cut­ting all the RNAs in the cell and ac­tu­al­ly de­stroy­ing the cell, which is not re­al­ly great” for mak­ing ther­a­pies, Abu­dayyeh told End­points News.

Eu­gene Koonin

So the pair piv­ot­ed and launched a com­pa­ny, Sher­lock, to turn Cas13 in­to easy-to-use di­ag­nos­tics for RNA-based virus­es, even­tu­al­ly in­clud­ing Covid-19. But they kept look­ing for some­thing that might of­fer a path to pa­tients, scan­ning pub­lished lit­er­a­ture and data­bas­es for any­thing that might cut RNA.

On that day in Que­bec, Eu­gene Koonin and Ki­ra Makaro­va, re­searchers known for pi­o­neer­ing work on CRISPR evo­lu­tion, sug­gest­ed that the pro­tein they were look­ing for might be out there, in one of the last places one would sus­pect.

Two years, a pan­dem­ic, a bit of pro­tein en­gi­neer­ing and ter­abytes of evo­lu­tion­ary bi­ol­o­gy lat­er, the four on Mon­day un­veiled a new CRISPR pro­tein: Cas7-11, so named be­cause it com­bines the oth­er­wise sep­a­rate pro­teins Cas7 and Cas11. In a Na­ture pa­per, they showed the new en­zyme could ac­cu­rate­ly ed­it RNA in mam­malian cells with­out dam­ag­ing the cell.

“They have a lot of work ahead of them but this is re­al­ly promis­ing,” Ran­jan Ba­tra, R&D chief of the RNA edit­ing biotech Lo­can­abio, told End­points. “These things have the po­ten­tial to be trans­for­ma­tion­al.”

Ki­ra Makaro­va

RNA edit­ing could be used to tar­get dis­eases rang­ing from in­fec­tious dis­ease to neu­rode­gen­er­a­tion, and Abu­dayyeh and Gooten­berg have plans for all that. But Cas7-11 is al­so no­tably for oth­er, nerdier — al­beit no less im­por­tant — rea­sons.

CRISPR is gen­er­al­ly re­ferred to as a sin­gle sys­tem, but it’s ac­tu­al­ly many dif­fer­ent ones. Dif­fer­ent species of bac­te­ria evolved them over eons as pow­er­ful tools to mem­o­rize and de­fend against dead­ly virus­es. Bi­ol­o­gists study­ing these sys­tems to­day cat­e­go­rize them as ei­ther class 1 or class 2.

Class 2 sys­tems can ed­it with just a sin­gle pro­tein. Cas9, Cas13, CasX, CasΦ and all the oth­er well-known Cas sys­tems now used across biotech and acad­e­mia be­long in this buck­et. When bi­ol­o­gists like Gooten­berg and Abu­dayyeh try to find new CRISPR pro­tein, they search bac­te­r­i­al genes for those that bear the unique ge­net­ic sig­na­tures of CRISPR type 1 sys­tem.

By con­trast, un­less you’re a CRISPR re­searcher or a cer­tain type of bac­te­ri­ol­o­gist, you’ve prob­a­bly nev­er heard of any of the class 1 pro­teins. These re­quire mul­ti­ple dif­fer­ent parts to come to­geth­er to cut DNA or RNA. And that makes them vir­tu­al­ly use­less for ther­a­peu­tics.

Ran­jan Ba­tra

Cas7-11, though, is dif­fer­ent. It’s a sin­gle edit­ing pro­tein, but, ge­net­i­cal­ly, it clear­ly evolved from class 1 sys­tems. And that means there are like­ly oth­er med­ical­ly valu­able CRISPR pro­teins sit­ting in bac­te­ria that re­searchers have over­looked for years.

“We’re show­ing that now, there’s a whole new stage that you can look for” CRISPR pro­teins, Abu­dayyeh said. “There’s prob­a­bly a lot of valu­able stuff out there.”

Har­vard bio­chemist David Liu said the dis­cov­ery was part of a decade-long trend, where re­searchers tapped bac­te­ria to find pro­teins with bet­ter and bet­ter at­trib­ut­es. Cas 7-11 was found in bac­te­ria iso­lat­ed from Tokyo Bay 22 years ago.

“It’s tempt­ing to spec­u­late that sta­ple CRISPR DNA- and RNA-tar­get­ing pro­teins such as Cas13, Cas12, or Cas9 might be su­per­seded, or at least fre­quent­ly re­placed, by the best of these new­ly dis­cov­ered CRISPR” pro­teins, Liu said in an email.

Gooten­berg and Abu­dayyeh en­vi­sion ap­ply­ing Cas7-11 in sev­er­al dif­fer­ent ar­eas. It could be used as an an­tivi­ral, snip­ping out an RNA-based virus like coro­n­avirus or HIV with­out touch­ing hu­man RNA. You could use it to tar­get and shred tu­mors. It could be used to delete ex­tra­ne­ous RNA in dis­eases like Hunt­ing­ton’s, where neu­rons churn out a sin­gle se­quence of RNA on re­peat un­til it de­stroys neu­rons. There are al­so ap­pli­ca­tions in re­gen­er­at­ing in­jured tis­sues.

The pair, how­ev­er, has a ways to go be­fore Cas 7-11 will be ready for pa­tients. Ba­tra, the Lo­canobio sci­en­tist, not­ed they on­ly showed Cas 7-11 was safer than the orig­i­nal Cas13. And they on­ly showed it was su­pe­ri­or in a cou­ple of cell lines, as op­posed to in peo­ple.

Lo­can­abio is us­ing en­gi­neered and new­ly dis­cov­ered forms of Cas13 to over­come its ini­tial draw­backs. They are now us­ing them to de­vel­op ther­a­pies for dis­eases marked by RNA re­peats, in­clud­ing Hunt­ing­ton’s, cer­tain mus­cu­lar dy­s­tro­phies, and ALS.

Ba­tra al­so not­ed that, un­like Lo­can­abio’s Cas13 en­zymes, Cas7-11 is cur­rent­ly too big to fit in­side the virus­es re­searchers gen­er­al­ly use to de­liv­er CRISPR to pa­tients. That could even­tu­al­ly build a small­er ver­sion, he said, but they haven’t yet.

“At this point,” he said, “I’m not sure what po­ten­tial ad­van­tages I see.”

Still, at min­i­mum, the dis­cov­ery has opened an­oth­er tool — and an­oth­er batch of in­tel­lec­tu­al prop­er­ty — for a new com­pa­ny to go af­ter RNA edit­ing.

The re­search pair li­censed Cas7-11 to a com­pa­ny in stealth mode. Ac­cord­ing to their con­flict of in­ter­est state­ments on the pa­per, that’s ei­ther Mo­ment Bio­sciences or Tome Bio­sciences, both based in Mass­a­chu­setts.

De­spite the cur­rent draw­backs, they have big hopes for the pro­tein. Its cu­ri­ous name de­rives both be­cause it com­bines the pro­tein Cas7 and Cas11, and be­cause of its res­o­nance with the fa­mous con­ve­nience chain.

“I have the email from Eu­gene [Koonin],” Gooten­berg said. “He’s like oh yeah, Cas7-11, it’s so great. Maybe it’ll one day be as ubiq­ui­tous as 7/11.”

Health­care Dis­par­i­ties and Sick­le Cell Dis­ease

In the complicated U.S. healthcare system, navigating a serious illness such as cancer or heart disease can be remarkably challenging for patients and caregivers. When that illness is classified as a rare disease, those challenges can become even more acute. And when that rare disease occurs in a population that experiences health disparities, such as people with sickle cell disease (SCD) who are primarily Black and Latino, challenges can become almost insurmountable.

David Meek, new Mirati CEO (Marlene Awaad/Bloomberg via Getty Images)

Fresh off Fer­Gene's melt­down, David Meek takes over at Mi­rati with lead KRAS drug rac­ing to an ap­proval

In the insular world of biotech, a spectacular failure can sometimes stay on any executive’s record for a long time. But for David Meek, the man at the helm of FerGene’s recent implosion, two questionable exits made way for what could be an excellent rebound.

Meek, most recently FerGene’s CEO and a past head at Ipsen, has become CEO at Mirati Therapeutics, taking the reins from founding CEO Charles Baum, who will step over into the role of president and head of R&D, according to a release.

Dave Lennon, former president of Novartis Gene Therapies

Zol­gens­ma patent spat brews be­tween No­var­tis and Re­genxbio as top No­var­tis gene ther­a­py ex­ec de­parts

Regenxbio, a small licensor of gene therapy viral vectors spun out from the University of Pennsylvania, is now finding itself in the middle of some major league patent fights.

In addition to a patent suit with Sarepta Therapeutics from last September, Novartis, is now trying to push its smaller partner out of the way. The Swiss biopharma licensed Regenxbio’s AAV9 vector for its $2.1 million spinal muscular atrophy therapy Zolgensma.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 117,600+ biopharma pros reading Endpoints daily — and it's free.

Volker Wagner (L) and Jeff Legos

As Bay­er, No­var­tis stack up their ra­dio­phar­ma­ceu­ti­cal da­ta at #ES­MO21, a key de­bate takes shape

Ten years ago, a small Norwegian biotech by the name of Algeta showed up at ESMO — then the European Multidisciplinary Cancer Conference 2011 — and declared that its Bayer-partnered targeted radionuclide therapy, radium-223 chloride, boosted the overall survival of castration-resistant prostate cancer patients with symptomatic bone metastases.

In a Phase III study dubbed ALSYMPCA, patients who were treated with radium-223 chloride lived a median of 14 months compared to 11.2 months. The FDA would stamp an approval on it based on those data two years later, after Bayer snapped up Algeta and christened the drug Xofigo.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 117,600+ biopharma pros reading Endpoints daily — and it's free.

Ex­elix­is pulls a sur­prise win in thy­roid can­cer just days ahead of fi­nal Cabome­tyx read­out

Exelixis added a thyroid cancer indication to its super-seller Cabometyx’s label on Friday — months before the FDA was expected to make a decision, and days before the company was set to unveil the final data at #ESMO21.

At a median follow-up of 10.1 months, differentiated thyroid cancer patients treated with Cabometyx (cabozantinib) lived a median of 11 months without their disease worsening, compared to just 1.9 months for patients given a placebo, Exelixis said on Monday.

Rafaèle Tordjman (Jeito Capital)

Con­ti­nu­ity and di­ver­si­ty: Rafaèle Tord­j­man's women-led VC firm tops out first fund at $630M

For a first-time fund, Jeito Capital talks a lot about continuity.

Rafaèle Tordjman had spotlighted that concept ever since she started building the firm in 2018, promising to go the extra mile(s) with biotech entrepreneurs while pushing them to reach patients faster.

Coincidentally, the lack of continuity was one of the sore spots listed in a report about the European healthcare sector published that same year by the European Investment Bank — whose fund is one of the LPs, alongside the American pension fund Teacher Retirement System of Texas and Singapore’s Temasek, to help Jeito close its first fund at $630 million (€534 million). As previously reported, Sanofi had chimed in €50 million, marking its first investment in a French life sciences fund.

Mi­rati tri­umphs again in KRAS-mu­tat­ed lung can­cer with a close­ly watched FDA fil­ing now in the cards

After a busy weekend at #ESMO21, which included a big readout for its KRAS drug adagrasib in colon cancer, Mirati Therapeutics is ready to keep the pressure on competitor Amgen with lung cancer data that will undergird an upcoming filing.

In topline results from a Phase II cohort of its KRYSTAL-1 study, adagrasib posted a response rate of 43% in second-line-or-later patients with metastatic non-small cell lung cancer containing a KRAS-G12C mutation, Mirati said Monday.

Den­mark's Gubra to col­lab­o­rate with Bay­er on pep­tides; Sam­sung and Bio­gen re­ceive FDA ap­proval for Lu­cen­tis biosim­i­lar

Danish biotech Gubra announced a research collaboration and license agreement with Bayer to develop peptide therapeutics to treat cardiorenal diseases. The collaboration will utilize Gubra’s peptide drug discovery platform to identify potential candidates.

This is not the first time Gubra has partnered with a company on peptide therapeutics — they partnered with Boehringer Ingelheim back in 2017 to create peptide therapeutics to treat obesity.

Ex-My­lan em­ploy­ee pleads guilty to in­sid­er trad­ing, il­le­gal­ly deal­ing on FDA ap­provals, earn­ings and Up­john merg­er

A former Mylan IT executive pleaded guilty Friday to an insider trading scheme where he bought and sold stock options on another executive’s advice.

Prosecutors secured the plea from Dayakar Mallu, Mylan’s former VP of global operations information technology, after uncovering the plan. Mallu collaborated with an unnamed “senior manager,” the SEC said, to trade options ahead of Mylan public announcements regarding FDA approvals, revenue reports and its merger with the Pfizer generics subsidiary Upjohn. The two subsequently shared profits.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 117,600+ biopharma pros reading Endpoints daily — and it's free.