Close­ly-watched in­ter­na­tion­al CRISPR ethics pan­el leaves door ajar for germline edit­ing — one day

In 2017, some of the world’s top sci­en­tists and ethi­cists emerged from over a year of de­lib­er­a­tions with a re­port meant to fi­nal­ly lay down guid­ing prin­ci­ples for how CRISPR, the awe­some-pow­er-awe­some-re­spon­si­bil­i­ty genome edit­ing tool, should be safe­ly and moral­ly used.

Then, just months lat­er, a sci­en­tist named He Jiankui an­nounced he had used the tool to ed­it em­bryos and cre­ate so-called “CRISPR ba­bies.” That was baf­fling to the ex­perts who uni­ver­sal­ly preached cau­tion, but so was his next claim: That he had done so while fol­low­ing the — in hind­sight, vague — prin­ci­ples set out in the re­port.

So the sci­en­tists went back to the draw­ing board. Less than two years af­ter the ini­tial project, the Na­tion­al Acad­e­my of Sci­ences launched a sec­ond pan­el to pro­duce a re­port less open to in­ter­pre­ta­tion.

Yes­ter­day, they re­leased the re­sults. Un­like the pre­vi­ous re­port, the new one starts with a list of de­clar­a­tive and un­am­bigous de­c­la­ra­tions: With­out clos­ing the door on edit­ing em­bryos, the pan­el con­clud­ed that the sci­en­tif­ic tools were not yet avail­able to do so safe­ly, and even when they were avail­able, they could on­ly be eth­i­cal­ly ap­plied in a nar­row set of cir­cum­stances. They al­so called for the cre­ation of in­ter­na­tion­al bod­ies that could coun­sel sci­en­tists and gov­ern­ments and track re­ports of sci­en­tists, such as He Jiankui, car­ry­ing out po­ten­tial­ly du­bi­ous projects.

One of the key points of con­tention around the 2017 re­port was the ques­tion of where germline edit­ing may one day be al­low­able. These types of ed­its are par­tic­u­lar­ly con­cern­ing be­cause, un­like edit­ing cells in an adult, the changes to the genome be­come her­i­ta­ble, al­ter­ing hu­man evo­lu­tion. There are al­so con­cerns around con­sent — the per­son be­ing edit­ed can’t give it. Still, the 2017 pan­el ruled that such an ed­it might be used in cas­es of “se­ri­ous, un­met med­ical need.” He in­ter­pret­ed that to cov­er a gene that af­fect­ed HIV trans­mis­sion. Many oth­er schol­ars did not.

The new guide­lines are far more tai­lored. Ini­tial us­es, they write, should be “lim­it­ed to se­ri­ous mono­genic dis­eases,” ones that “cause se­vere mor­bid­i­ty or death.” That could in­clude mus­cu­lar dy­s­tro­phy, be­ta-tha­lassemia, cys­tic fi­bro­sis, and Tay-Sachs dis­ease, among oth­ers, they write. No­tably, they ex­clude dis­eases caused by mul­ti­ple genes, even when a par­tic­u­lar gene vari­ant such as APOE4 in Alzheimer’s puts some­one at a greater risk of de­vel­op­ing that dis­ease. APOE4, they note, on­ly cor­re­lates with a 5% greater risk of Alzheimer’s be­tween ages 60 and 69.

Richard Lifton

“Edit­ing a gene vari­ant as­so­ci­at­ed with a com­plex dis­ease is like­ly to have on­ly a mi­nor ef­fect on the risk of de­vel­op­ing that dis­ease,” the re­port’s au­thors, chaired by Ox­ford’s Kay Davies and Rock­e­feller Uni­ver­si­ty’s Richard Lifton, write, “while al­so po­ten­tial­ly in­tro­duc­ing un­known ef­fects be­cause of oth­er bi­o­log­i­cal roles the gene may play and oth­er ge­net­ic net­works in which it may in­ter­act.”

Even in cas­es of se­vere mono­genic dis­eases, though, CRISPR use would be se­vere­ly cur­tailed. With IVF and neo-na­tal screen, doc­tors can al­ready screen em­bryos for Tay-Sachs and oth­er con­di­tions and se­lect the best ones. So such ed­its would on­ly be per­mis­si­ble in cas­es where there are no al­ter­na­tives, such as when every one of a prospec­tive par­ent’s em­bryos car­ry the ge­net­ic vari­ant. The ed­it would al­so have to cor­rect a vari­ant in­to the com­mon form of the gene, elim­i­nat­ing the form of edit­ing He used, where he tried to crip­ple the CCR5 gene HIV us­es to en­ter cells.

And edit­ing for those dis­or­ders would on­ly be per­mis­si­ble once sci­en­tif­ic tech­niques catch up to these sci­en­tif­ic ideas, the au­thors wrote, which they haven’t. Sci­ence writ­ers have com­pared us­ing CRISPR to edit­ing the hu­man genome like a Word doc­u­ment, but it might be more apt to com­pare it to edit­ing a Word doc­u­ment on cof­fee-stained key­board. It works of­ten, but in­vari­ably there are un­want­ed changes both at the site of the ed­it and oth­er sites on the genome.

The re­port warns strong­ly against germline edit­ing be­fore re­searchers de­vel­op meth­ods to not on­ly sys­tem­at­i­cal­ly ed­it em­bryos with­out those un­in­tend­ed changes, but to ad­e­quate­ly screen the em­bryos to as­sure they’ve been edit­ed safe­ly.

Kay Davies

“No at­tempt to es­tab­lish a preg­nan­cy with a hu­man em­bryo that has un­der­gone genome edit­ing should pro­ceed un­less and un­til it has been clear­ly es­tab­lished that it is pos­si­ble to ef­fi­cient­ly and re­li­ably make pre­cise ge­nom­ic changes with­out un­de­sired changes in hu­man em­bryos,” they write in rec­om­men­da­tion #1. “These cri­te­ria have not yet been met and fur­ther re­search and re­view would be nec­es­sary to meet them.”

While cau­tion­ing that de­ci­sions on germline edit­ing are left to in­di­vid­ual coun­tries, the re­port calls for in­ter­na­tion­al bod­ies that could set rec­om­men­da­tions and man­age re­ports of un­eth­i­cal be­hav­ior. That would in­clude an In­ter­na­tion­al Sci­en­tif­ic Ad­vi­so­ry Pan­el with “di­verse, mul­ti­dis­ci­pli­nary mem­ber­ship” and “in­de­pen­dent ex­perts who can as­sess sci­en­tif­ic ev­i­dence of safe­ty and ef­fi­ca­cy of both genome edit­ing and as­so­ci­at­ed as­sist­ed re­pro­duc­tive tech­nolo­gies.” That pan­el would give in­sight be­fore any new form of germline edit­ing was used in hu­mans.

The un­spec­i­fied body for re­port­ing un­eth­i­cal be­hav­ior would pass those con­cerns to na­tion­al au­thor­i­ties and pub­licly dis­close them. No­tably, mul­ti­ple sci­en­tists knew of He’s work be­fore the an­nounce­ment but said they lacked au­thor­i­ties to re­port to.

Since He’s an­nounce­ment – which ul­ti­mate­ly land­ed him a 3-year prison sen­tence in Chi­na — there have been no oth­er known cas­es of a re­searcher edit­ing an em­bryo be­fore preg­nan­cy. A Russ­ian sci­en­tist, though, has pur­sued a project to cor­rect blind­ness in em­bryos, rais­ing sim­i­lar alarm among out­side ex­perts. He told Sci­ence’s Jon Co­hen he op­posed the new rec­om­men­da­tions as “far too nar­row.”

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

Stéphane Bancel, Moderna CEO

'This is not go­ing to be good': Mod­er­na CEO Ban­cel warns of a 'ma­te­r­i­al drop' in vac­cine ef­fi­ca­cy as Omi­cron spreads

Even as public health officials remain guarded about their comments on the likelihood Omicron will escape the reach of the currently approved Covid-19 vaccines, there’s growing scientific consensus that we’re facing a variant that threatens to overwhelm the vaccine barricades that have been erected.

Stéphane Bancel, the CEO of Moderna, one of the leading mRNA players whose quick vault into the markets with a highly effective vaccine created an instant multibillion-dollar market, added his voice to the rising chorus early Tuesday. According to Bancel, there will be a significant drop in efficacy when the average immune system is confronted by Omicron. The only question now is: How much?

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Philip Dormitzer, new GSK global head of vaccines R&D

Glax­o­SmithK­line poach­es Pfiz­er's vi­ral vac­cines lead in rush to cap­i­tal­ize on fu­ture of mR­NA

GlaxoSmithKline has appointed Philip Dormitzer, formerly chief scientific officer of Pfizer’s viral vaccines unit, as its newest global head of vaccines R&D, looking to leverage one of the leading minds behind Pfizer and BioNTech’s RNA collaboration that led to Covid-19 jab Comirnaty, the British drug giant said Tuesday.

Dormitzer had been with Pfizer for a little more than six years, joining up after a seven-year stint with Novartis, where he reached the role of US head of research and head of global virology for the company’s vaccines and diagnostics unit.

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In­tro­duc­ing End­points Stu­dio, a new way to ad­ver­tise with End­points-craft­ed brand­ing cam­paigns

Since our start in 2016, Endpoints has grown fast while executing our mission to cover biopharma’s most critical developments for industry pros worldwide. As readership has grown, our advertising business has too. Endpoints advertising partners support the mission and engage their desired audiences through announcements on our email and web platforms, brand recognition in our event coverage and sponsorships of Endpoints daily and weekly reports.

Tillman Gerngross (Adagio)

Till­man Gern­gross on Omi­cron: 'It is a grim sit­u­a­tion...we’re go­ing to see a sig­nif­i­cant drop in vac­cine ef­fi­ca­cy'

Tillman Gerngross, the rarely shy Dartmouth professor, biotech entrepreneur and antibody expert, has been warning for over a year that the virus behind Covid-19 would likely continue to mutate, potentially in ways that avoid immunity from infection and the best defenses scientists developed. He spun out a company, Adagio, to build a universal antibody, one that could snuff out any potential mutation.

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In­cor­po­rat­ing Ex­ter­nal Da­ta in­to Clin­i­cal Tri­als: Com­par­ing Dig­i­tal Twins to Ex­ter­nal Con­trol Arms

Most drug development professionals are familiar with the nerve-racking wait for the read-out of a large trial. If it’s negative, is the investigational therapy ineffective? Or could the failure result from an unforeseen flaw in the design or execution of the protocol, rather than a lack of efficacy? The team could spend weeks analyzing data, but a definitive answer may be elusive due to insufficient power for such analyses in the already completed trial. These problems are only made worse if the trial had lower enrollment, or higher dropout than expected due to an unanticipated event like COVID-19. And if a trial is negative, the next one is likely to be larger and more costly — if it happens at all.

Mar­ket­ingRx roundup: Ab­b­Vie’s Hu­mi­ra TV turns fo­cus to HS skin con­di­tion; Sanofi amps par­ent­ing pol­i­cy

After years as the top spending pharma TV advertiser, AbbVie’s Humira brand finally downshifted earlier this year, ceding much of its marketing budget to up-and-coming sibling meds Skyrizi and Rinvoq. However, now Humira is back on TV with ads for another condition — Hidradenitis suppurativa (HS).

The chronic and painful skin condition results in lumps and abscesses caused by inflammation or infection of sweat glands, most often in the armpits or groin. Humira was first approved to treat HS in 2015 and remains the only FDA-approved drug for the condition. Two TV ads both note more than 30,000 people with HS have been prescribed Humira.

As lead drug runs in­to a wall, De­ci­phera slims down its pipeline, puts 140 jobs on the chop­ping block

Barely a month after disappointing data shattered hopes for a major label expansion for the GI tumor drug Qinlock, Deciphera is making a major pivot — scrapping development plans for that drug and discarding another while it hunkers down and focuses on two remaining drugs in the pipeline.

As a result, 140 of its staffers will be laid off.

The restructuring, which claims the equivalent of 35% of its total workforce, will take place across all departments including commercial, R&D as well as general and administrative support functions, Deciphera said, as it looks to streamline Qinlock-related commercial operations in the US while concentrating only on a “select number of key European markets.”

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FDA can­cels ODAC meet­ing this week to re­view two more dan­gling ac­cel­er­at­ed ap­provals — but won't ex­plain why

The FDA’s Oncologic Drugs Advisory Committee has decided to cancel a planned meeting on Thursday to discuss two cancer drugs that previously won accelerated approvals but failed to confirm clinical benefit in required follow-up trials or have taken a long time to finish those trials.

The FDA said in a statement that the meeting “is no longer needed” but did not offer further detail on why exactly it was canceled, telling Endpoints News to contact the companies. Attempts to contact both Secura Bio and Acrotech went unreturned. The companies may have decided to pull these treatments from the market, or they’ve come to new agreements with the agency on their confirmatory trials.