Jennifer Doudna, AP Images

Hit­ting land­mark mile­stone, In­tel­lia shows CRISPR can ed­it genes di­rect­ly in pa­tients

In a land­mark study, re­searchers suc­cess­ful­ly used CRISPR to di­rect­ly ed­it DNA in hu­mans, a mile­stone that could pave the way for treat­ments for scores of se­ri­ous ge­net­ic and non-ge­net­ic dis­eases.

In­tel­lia, a biotech co-found­ed by 2020 No­bel lau­re­ate Jen­nifer Doud­na, used CRISPR/Cas9 to cut a gene out of the liv­er cells of pa­tients with AT­TR amy­loi­do­sis, a dead­ly dis­ease where a mis­shapen pro­tein called TTR builds up and dam­ages or­gans through­out the body. Pa­tients who re­ceived a high dose of the ther­a­py saw their pro­tein lev­els fall be­tween 80% and 96%, in­di­cat­ing the ther­a­py per­ma­nent­ly cut the genome where de­sired.

The Phase I re­sults were pub­lished Sat­ur­day in the New Eng­land Jour­nal of Med­i­cine and pre­sent­ed at a sci­en­tif­ic con­fer­ence.

“This is the re­sult that the field has been wait­ing for to re­al­ly scale up,” Fy­o­dor Urnov, a gene edit­ing ex­pert at UC Berke­ley who was not af­fil­i­at­ed with the work, told End­points News. “If any­one had a shred of doubt, that there was a fu­ture in CRISPR edit­ing as a ther­a­peu­tic that will have a broad im­pact, those doubts can be put to rest.”

This is not the first time CRISPR has been used as a ther­a­py. Ver­tex and CRISPR Ther­a­peu­tics have used it to ef­fec­tive­ly treat sick­le cell dis­ease and be­ta-tha­lassemia. Aca­d­e­mics and oth­er com­pa­nies have, with some­what less suc­cess, used it in treat­ments for can­cer and HIV. But in each case, re­searchers re­moved blood stem cells from the pa­tients, edit­ed them in a lab and then re­turned them to the pa­tient — a sim­pler, safer and more con­trol­lable pro­ce­dure.

Most con­di­tions, though, can’t be ad­dressed by edit­ing cells out­side the body. Dev­as­tat­ing ge­net­ic dis­eases such as cys­tic fi­bro­sis and Duchenne mus­cu­lar dy­s­tro­phy could be treat­ed through CRISPR gene edit­ing, but on­ly if re­searchers can de­liv­er the ther­a­py di­rect­ly in­to pa­tients. The same holds true for some of the more com­mon ail­ments where com­pa­nies are now try­ing to ap­ply the tech­nol­o­gy, such as heart dis­ease.

On Sat­ur­day, In­tel­lia be­came the first to pull it off. Doud­na hailed it as a proof-of-con­cept for the en­tire field.

“While these are ear­ly da­ta, they show us that we can over­come one of the biggest chal­lenges with ap­ply­ing CRISPR clin­i­cal­ly so far, which is be­ing able to de­liv­er it sys­tem­i­cal­ly and get it to the right place,” Doud­na said in an email. “It’s a crit­i­cal first step in be­ing able to in­ac­ti­vate, re­pair or re­place any gene that caus­es dis­ease, any­where in the body. This opens up the pos­si­bil­i­ty to treat a wide range of dis­eases that we haven’t been able to ad­dress so far.”

In­tel­lia’s stock $NT­LA jumped 52% when pre-mar­ket trad­ing be­gan Mon­day, rais­ing their mar­ket cap by $3 bil­lion. The oth­er so-called “CRISPR com­pa­nies,” in­clud­ing Beam, CRISPR Ther­a­peu­tics, and Ed­i­tas, all rose be­tween 15% and 25%.

In­tel­lia be­gan work­ing on the AT­TR pro­gram not long af­ter it was found­ed in 2014, said CEO John Leonard. They tin­kered for years, af­ter the first ver­sions edit­ed less than 2% of tar­get­ed cells in mice. Even­tu­al­ly, they de­vised two RNA strands, one that codes for the DNA-cut­ting en­zyme Cas9 and an­oth­er, the guide RNA, that tells Cas9 which gene to cut.

Lau­ra Sepp-Loren­zi­no

They en­cased the RNA in a lipid nanopar­ti­cle, the mi­cro­scop­ic bub­bles of fat that have now been used around the world to de­liv­er mR­NA Covid-19 vac­cines. Af­ter the LNPs are ad­min­is­tered to pa­tients, they go to the liv­er, ex­press Cas9, which slices the DNA, and flush out with­in hours, said CSO Lau­ra Sepp Loren­zi­no.

“Part of our de­sign cri­te­ria was rapid elim­i­na­tion,” Loren­zi­no told End­points.

The first three AT­TR pa­tients, who re­ceived a low dose of the ther­a­py, saw their pro­duc­tion of TTR pro­tein fall by an av­er­age of 57%. When they es­ca­lat­ed for the next three pa­tients, they saw an av­er­age re­duc­tion of 87%.

The lat­ter fig­ure close­ly ri­vals the da­ta from Al­ny­lam’s RNAi drug On­pat­tro, one of three drugs re­cent­ly ap­proved for the dis­ease. But In­tel­lia’s ap­proach on­ly has to be dosed once in a life­time, as op­posed to once every three weeks.

“The lev­el of TTR pro­tein re­duc­tion is im­pres­sive,” Har­vard bio­chemist David Liu, who co-found­ed CRISPR com­pa­nies Beam and Prime, said in an email. The da­ta “serve as a com­pelling re­minder that the era of in vi­vo ther­a­peu­tic hu­man gene edit­ing is al­ready up­on us.”

David Liu

Liu not­ed In­tel­lia got re­sults de­spite us­ing less than 1/10th the dose they used in mon­keys. The com­pa­ny plans to up the dosage fur­ther to try to com­plete­ly elim­i­nate pro­tein pro­duc­tion — a bench­mark they hope will not on­ly stop the dis­ease’s pro­gres­sion but po­ten­tial­ly re­verse it, giv­ing the body time to clean up that mis­shapen pro­tein that ac­cu­mu­lat­ed in the years pri­or to ther­a­py.

Out­side ex­perts took par­tic­u­lar note of the safe­ty da­ta. It was not clear what would hap­pen when re­searchers first ad­min­is­tered Cas9, a pro­tein de­rived from bac­te­ria, through­out the body. Some feared that the im­mune sys­tem would rec­og­nize it as for­eign and go in­to dan­ger­ous over­drive.

“The safe­ty da­ta look re­al­ly good,” Alex­is Ko­mor, who runs a gene edit­ing lab at UC San Diego, told End­points. “There’s no crazy im­mune re­sponse. That was a ques­tion that every­body’s had for a while.”

Alex­is Ko­mor

Still, there are key safe­ty ques­tions that can on­ly be an­swered with time. Over the last decade, CRISPR re­searchers have doc­u­ment­ed in nu­mer­ous lab stud­ies that, by break­ing the DNA in two, Cas9 can in­flict un­in­tend­ed dam­age on the genome.

So far those have not born out in pa­tients and ex­perts say there are no red flags in In­tel­lia’s da­ta. But it will be hard­er for In­tel­lia to mon­i­tor than for pre­vi­ous com­pa­nies who edit­ed blood cells; they were able to check in the lab how the cells re­spond­ed ini­tial­ly and take sub­se­quent sam­ples from pa­tients to mon­i­tor.

By con­trast, doc­tors can’t just re­move a pa­tient’s liv­er to mon­i­tor for ear­ly signs of can­cer. “There’s just a fun­da­men­tal ques­tion of how we do long-term fol­lowup,” Urnov said.

The com­pa­ny will now look to ap­ply the same strat­e­gy they used for AT­TR to an­oth­er ge­net­ic dis­ease, hered­i­tary an­gioede­ma, swap­ping out the guide RNA for TTR and re­plac­ing it with one for a gene called KLB1.

Fy­o­dor Urnov

Urnov said the tech­nol­o­gy will work like mR­NA vac­cines: Once proven, the plat­form can be re­de­ployed for an­oth­er dis­ease by swap­ping out one set of ge­net­ic in­struc­tions for an­oth­er. It pro­vides a proof of prin­ci­ple for Verve Ther­a­peu­tics, which is try­ing to pre­vent heart dis­ease by knock­ing out a gene in the liv­er that strong­ly af­fects cho­les­terol lev­els.

For these com­pa­nies, he said, “the ball is in your court,” he said, “to do it and just not drop the ball.”

But that on­ly ap­plies to a sub­set of ther­a­pies and dis­eases. In­tel­lia ef­fec­tive­ly went af­ter the low­est hang­ing fruit for sys­temic CRISPR treat­ments. They di­rect­ed the treat­ment against the liv­er, the body’s in­ter­nal fil­ter and the eas­i­est or­gan to di­rect ge­net­ic ther­a­pies. And they on­ly tried to crip­ple a gene, rather than re­pair one.

To tack­le most of the dis­eases sci­en­tists en­vi­sioned cur­ing when CRISPR was first pi­o­neered a decade ago, re­searchers will have to prove they can de­liv­er through­out the body and, once there, turn a mu­tant gene in­to a healthy one — a pair of sig­nif­i­cant­ly high­er hur­dles.

Rodolphe Bar­ran­gou

Ear­ly tests for those hur­dles will ar­rive in the com­ing years, as ther­a­pies for Duchenne and HIV, among oth­ers, en­ter the clin­ic.

“It’s an ex­cit­ing day, it’s an ex­cit­ing mile­stone,” Rodolphe Bar­ran­gou, an ear­ly CRISPR re­searcher and a co-founder of In­tel­lia, told End­points. “But we have a ways to go.”

Adap­tive De­sign Meth­ods Of­fer Rapid, Seam­less Tran­si­tion Be­tween Study Phas­es in Rare Can­cer Tri­als

Rare cancers account for 22 percent of cancer diagnoses worldwide, yet there is no universally accepted definition for a “rare” cancer. Moreover, with the evolution of genomics and associated changes in categorizing tumors, some common cancers are now characterized into groups of rare cancers, each with a unique implication for patient management and therapy.

Adaptive designs, which allow for prospectively planned modifications to study design based on accumulating data from subjects in the trial, can be used to optimize rare oncology trials (see Figure 1). Adaptive design studies may include multiple cohorts and multiple tumor types. In addition, numerous adaptation methods may be used in a single trial and may facilitate a more rapid, seamless transition between study phases.

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