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.”

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Chamath Palihapitiya and Pablo Legorreta

Bil­lion­aires Chamath Pal­i­hapi­tiya and Pablo Legor­re­ta hatch an $825M SPAC for cell ther­a­py biotech

Three years after Royalty Pharma chief Pablo Legorreta led a group of investors to buy up a pair of biotechs and create a new startup called ProKidney, the biotech is jumping straight into an $825 million public shell created by SPAC king and tech billionaire Chamath Palihapitiya.

ProKidney was founded 6 years ago but really got going at the beginning of 2019 with the $62 million acquisition of inRegen, which was working on an autologous — from the patient — cell therapy for kidney disease. After extracting kidney cells from patients, researchers expand the cells in the lab and then inject them back into patients, aiming to restore the kidneys of patients suffering from CKD.

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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.

Joshua Brumm, Dyne Therapeutics CEO

FDA or­ders DMD tri­al halt, rais­ing ques­tions about a whole class of promis­ing drugs

Dyne Therapeutics’ stock took a nasty hit this morning after the biotech put out word that the FDA had slapped a clinical hold on their top program for Duchenne muscular dystrophy. And now speculation is bouncing around Biotwitter that there could be a class effect at work here that would implicate other drug developers in the freeze.

Dyne execs didn’t have a whole lot to say about why the FDA sidelined their IND for DYNE-251 in DMD while “requesting additional clinical and non-clinical information for” the drug.

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CEO Lex Rovner (64x Bio)

A George Church spin­out fight­ing the vi­ral vec­tor bot­tle­neck in cell and gene ther­a­py lands $55M

A synthetic biology company spun out of George Church’s lab is set to tackle the gene therapy manufacturing bottleneck, and it just landed $55 million in a Series A financing round to do so.

64x Bio comes out of the Harvard Department of Genetics. CEO Lex Rovner and her team — which right now, sits around 10 people — are looking to tackle a key hurdle for major companies: manufacturing cell and gene therapies.