David Liu, Broad Institute

Re­ly­ing on an ul­tra-rare vari­ant, David Liu un­veils a new ap­proach to edit­ing sick­le cell

There are now at least five dif­fer­ent ap­proach­es to cur­ing sick­le cell in or near­ing hu­man test­ing from at least eight dif­fer­ent com­pa­nies or aca­d­e­m­ic cen­ters. But re­searchers have not stopped look­ing for im­prove­ments.

David Liu, the co-in­ven­tor of base edit­ing and co-founder of Beam Ther­a­peu­tics, un­veiled in Na­ture Tues­day a new ap­proach for us­ing gene edit­ing to turn pa­tients’ sick­ling he­mo­glo­bin in­to a healthy form of the pro­tein. If it plays out in hu­mans, ex­perts say, the strat­e­gy could of­fer a more di­rect and po­ten­tial­ly safer way of treat­ing the de­bil­i­tat­ing ge­net­ic dis­ease.

“It’s a step for­ward,” said Ste­fano Riv­el­la, who works on gene-based cures for blood dis­or­ders at Chil­dren’s Hos­pi­tal of Philadel­phia and was not in­volved in the study. “It’s very promis­ing and def­i­nite­ly some­thing nov­el com­pared to the oth­er tech­nolo­gies.”

Over the last half-decade, com­pa­nies have large­ly re­lied on two gene-based strate­gies for treat­ing sick­le cell, nei­ther of which ac­tu­al­ly deal with the mu­ta­tion di­rect­ly. Blue­bird bio us­es gene ther­a­py to give pa­tients a func­tion­ing, lab-syn­the­sized copy of the gene. And the var­i­ous CRISPR com­pa­nies — CRISPR Ther­a­peu­tics, Ed­i­tas and In­tel­lia — all use a cre­ative workaround: They shat­ter a gene that stops peo­ple from mak­ing fe­tal he­mo­glo­bin, the form of the pro­tein that most peo­ple stop mak­ing in in­fan­cy. In sick­le cell pa­tients who re­ceive the treat­ment, the fe­tal he­mo­glo­bin turns back on and be­gins fer­ry­ing oxy­gen around the body.

Both ap­proach­es have yield­ed func­tion­al cures in the clin­ic, clear­ing dozens of pa­tients of the dev­as­tat­ing pain crises that are the hall­mark of the dis­ease. But they al­so come with risks that, while not yet seen in hu­mans, have been well es­tab­lished in the lab.

To de­liv­er its gene, blue­bird re­lies on lentivirus, a re-en­gi­neered form of HIV that in­te­grates ran­dom­ly in­to a pa­tients’ DNA and could in­ter­fere with genes that sup­press tu­mors. CRISPR breaks the DNA in half, rais­ing sim­i­lar con­cerns about how the frac­ture could re­ver­ber­ate across the genome.

“I’m def­i­nite­ly con­cerned,” said Hans-Pe­ter Kiem, a gene edit­ing re­searcher at Fred Hutch. “It’s a the­o­ret­i­cal risk, but I’m def­i­nite­ly con­cerned.”

De­spite clin­i­cal suc­cess, those con­cerns have on­ly grown in the last cou­ple of years, as re­searchers spot­light­ed new ways CRISPR cuts could the­o­ret­i­cal­ly man­gle the genome: re­ar­rang­ing chro­mo­somes, for ex­am­ple, or in­ter­act­ing in pre­vi­ous­ly un­fore­seen ways with par­tic­u­lar ge­net­ic vari­ants com­mon in peo­ple with African an­ces­try.

“We have not seen any­thing yet (in the clin­ic),” said Fy­o­dor Urnov, a gene edit­ing re­searcher at UC-Berke­ley. “But this is the clas­sic ex­am­ple of where ab­sence of ev­i­dence is not ev­i­dence of ab­sence.”

Liu and a post­doc, Greg New­by, tried to find a way to fix the mu­ta­tion more di­rect­ly, with­out break­ing any­thing. That’s not a straight­for­ward task. Sick­le cell is caused by a change at a sin­gle base: a switch from A to T. Base edit­ing, the strat­e­gy Liu pi­o­neered in 2016, al­lows re­searchers to swap one base for an­oth­er with­out break­ing the dou­ble-he­lix, but it on­ly works for a frac­tion of com­bi­na­tions. T-A isn’t one of them.

In­stead, Liu and New­by de­signed a base ed­i­tor that would turn the T in­to a C, mim­ic­k­ing an ul­tra-rare he­mo­glo­bin vari­ant first iden­ti­fied in Makas­sar, In­done­sia. De­spite the mu­ta­tion, peo­ple make func­tion­al he­mo­glo­bin and live healthy lives.

“It’s sim­ply a sim­pler and more di­rect way,” Liu said. They’re “con­vert­ing a gene vari­ant that caus­es the dis­ease to one that we know ex­ists in peo­ple who are healthy.”

Work­ing with Mitchell Weiss’ lab at St. Jude, Liu and Win­ters used an elec­tric cur­rent to get ed­i­tor in­to stem cells from hu­man donors, suc­cess­ful­ly cor­rect­ing 80% of them. They did the same with mice — re­mov­ing, edit­ing and trans­plant­i­ng stem cells back in­to mice, where they per­sist­ed and were func­tion­al for 16 weeks. They then took stem cells from those mice and trans­plant­ed them in­to new mice — a way of prov­ing that the edit­ed cells had tru­ly sup­plant­ed them. Even the mice who had un­der­gone “sec­ondary trans­plan­ta­tion” pro­duced 70% edit­ed he­mo­glo­bin.

The ap­proach is high­ly sim­i­lar to one Beam Ther­a­peu­tics un­veiled in late April, when the com­pa­ny showed da­ta on edit­ing the Makas­sar mu­ta­tion in­to cell lines. Beam CSO Giuseppe Cia­ramel­la said they would take their own ap­proach in­to the clin­ic, but that Liu’s pro­vid­ed a proof-of-con­cept in an­i­mals.

“It demon­strates that this Makas­sar pro­tein is like the nor­mal and func­tion­al­ly cures the dis­ease,” he said.

Cia­ramel­la said Beam planned to de­vel­op both the Makas­sar ap­proach and their own base-edit­ed fe­tal he­mo­glo­bin ap­proach and, af­ter ear­ly stud­ies, de­cide which one to bring in­to a piv­otal tri­al. The fe­tal he­mo­glo­bin strat­e­gy, called Beam-101, should en­ter the clin­ic this year, he said, with the Makas­sar not far be­hind.

The hope is that the Makas­sar can pro­vide more ben­e­fits than just safe­ty. Cia­ramel­la not­ed that al­though fe­tal he­mo­glo­bin has been proven to ef­fec­tive­ly elim­i­nate pa­tients’ pain crises, many of the dis­ease’s worst ef­fects – in­clud­ing life ex­pectan­cy in the mid-40s — come not from crises, but from or­gan dam­age that builds up over time.

Pa­tients who re­ceive gene edit­ing ther­a­py to pro­duc­ing fe­tal he­mo­glo­bin con­tin­ue to al­so pro­duce sick­ling he­mo­glo­bin. It’s pos­si­ble that elim­i­nat­ing sick­ling he­mo­glo­bin — or at least as much sick­ling he­mo­glo­bin as pos­si­ble — could fur­ther re­duce the risk of dam­age.

“The da­ta for el­e­vat­ing fe­tal he­mo­glo­bin look very im­pres­sive, but they’re re­cent,” said Urnov, who is al­so de­vel­op­ing a CRISPR-based strat­e­gy for di­rect­ly cor­rect­ing he­mo­glo­bin. “The gene ther­a­py da­ta look very im­pres­sive. They’re al­so very re­cent.”

Urnov added that com­pa­nies and the med­ical world had an oblig­a­tion to bring as many op­tions for­ward as pos­si­ble for sick­le cell, a dis­ease that pri­mar­i­ly af­fects African Amer­i­cans and where pa­tients have long been ig­nored by drug de­vel­op­ers and faced sys­temic dis­crim­i­na­tion when try­ing to seek treat­ment.

Liu’s strat­e­gy, though, doesn’t solve all the prob­lems with the first gen­er­a­tion of sick­le cell gene ther­a­pies. Riv­el­la not­ed that, while their strat­e­gy re­duces off-tar­get ed­its, it doesn’t elim­i­nate them en­tire­ly.

It al­so doesn’t get at the biggest risk that’s al­ready shown it­self in hu­mans: The in­ten­sive con­di­tion­ing that pa­tients in every tri­al have to go through be­fore re­ceiv­ing their edit­ed cells. The chemother­a­py used, busul­fan, has been linked in the past to can­cers and ex­perts now sus­pect it may al­so have helped trig­ger the cas­es of leukemia and myelodys­plas­tic syn­drome blue­bird re­cent­ly saw in its sick­le cell tri­als.

Kiem said he could en­vi­sion us­ing Liu’s strat­e­gy with the in-vi­vo ap­proach he is try­ing to de­vel­op, which would elim­i­nate the need for any kind of con­di­tion­ing. And oth­er com­pa­nies are try­ing to de­vel­op gen­tler al­ter­na­tives busul­fan. The ef­forts, though, re­main ear­ly stage.

“As long as peo­ple use busul­fan,” Riv­el­la said. “It doesn’t mat­ter if you use gene ad­di­tion, gene edit­ing, or base edit­ing. The prob­lem will be there.”

The Fac­tors Dri­ving a Rapid Evo­lu­tion of Gene & Cell Ther­a­py and CAR-T Clin­i­cal Re­search in APAC

APAC is the fastest growing region globally for cell & gene therapy trials representing more than a third of all cell & gene studies globally, with China leading in the region. 

APAC is the leading location globally for CAR-T trials with China attracting ~60% of all CAR-T trials globally between 2015-2022. The number of CAR-T trials initiated by Western companies has rapidly increased in recent years (current CAGR of about 60%), with multiple targets being explored including CD19, CD20, CD22, BCMA, CD30, CD123, CD33, CD38, and CD138.

The End­points 11; blue­bird's $3M gene ther­a­py; Bio­gen tout new neu­ro da­ta; Harsh re­views for can­cer drugs; 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.

Reading about John Carroll’s pick of biotech’s most promising startups has become a treasured tradition. If you ever get curious about previous classes of the Endpoints 11, you can find all of them (plus a number of our other regular specials) here.

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EMA warns of short­ages of two Boehringer heart drugs due to a spike in de­mand

The EMA is putting EU member states on alert over the shortage of two drugs that counter heart attacks due to an uptick in demand.

On Friday, the EMA sent out a warning that two Boehringer Ingelheim drugs are experiencing a shortage: Actilyse and Metalyse. The drugs are used as emergency treatments for adults experiencing acute myocardial infarction, or a heart attack, by dissolving blood clots that have formed in the blood vessels.

The End­points 11: The top pri­vate biotechs in pur­suit of new drugs. Push­ing the en­ve­lope with pow­er­ful new tech­nolo­gies

Right around the beginning of the year, we got a close-up look at what happens after a boom ripples through biotech. The crash of life sciences stocks in Q1 was heard around the world.

In the months since, we’ve seen the natural Darwinian down cycle take effect. Reverse mergers made a comeback, with more burned out shells to go public at a time IPOs and road shows are out of favor. And no doubt some of the more recent arrivals on the investing side of the business are finding greener pastures.

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Jim Wells (UCSF)

An­ti­bod­ies once act­ed on­ly as pro­tein block­ers. Now, sci­en­tists are find­ing new ways to make them pro­tein de­stroy­ers

The first lab-made antibody medicine was approved in 1986 — it bound to an antigen known as CD3 on T cells and was meant to prevent kidney transplant rejection. While antibody technology improved, most antibodies were made as blocking agents, neutering clamps that attacked cells and proteins.

But then scientists got creative with their engineering. They made antibody-drug conjugates, or ADCs for short, which attached toxins or drugs to the antibodies, enabling them to kill cells. Then they made CAR-T therapies, which attached a patient’s T cell to the targeting fragment of an antibody, to destroy cancer cells.

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As­traZeneca, Mer­ck cull one Lyn­parza in­di­ca­tion in heav­i­ly pre­treat­ed ovar­i­an can­cer pa­tients

Just one day after blockbuster Lynparza got access to another indication in China, its Big Pharma owners have decided to withdraw it in certain patients after reviewing Phase III data.

The two companies that work together on Lynparza decided to recall one of the indications several weeks ago in a specific type of ovarian cancer, Lynparza’s first indication when it was first FDA-approved in 2014. Initial data showed that rates of overall survival in patients with at least three rounds of chemo before getting on the PARP inhibitor were lower than in patients with less previous chemo treatment.

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Fu­ji­film con­tin­ues CD­MO ex­pan­sion, break­ing ground on $435M UK site

Fujifilm’s CDMO arm, Fujifilm Diosynth, has been on a roll this month as the company has recently broken ground on a major project in Europe and it appears to be keeping up the momentum.

Fujifilm Diosynth announced that it has kicked off an expansion project for its microbial manufacturing facility at its campus in the town of Billingham, UK, in the northeast of England.

The 20,000 square-foot, £400 million ($435 million) expansion will add clean rooms, purification suites and a packing area along with more space for the manufacturing itself.

Solicitor General Elizabeth Prelogar

Should SCO­TUS hear Am­gen's Repatha case? So­lic­i­tor gen­er­al says no

Back in April, Amgen said it was encouraged by the solicitor general’s anticipated review of its Supreme Court petition to rehear a Repatha patent case. They’re likely much less optimistic about the outcome now.

Solicitor General Elizabeth Prelogar wrote in a recent 27-page brief that Amgen’s arguments “lack merit and further review is not warranted.”

The case traces back to a suit filed in 2014 against Sanofi and Regeneron’s Praluent, which ended up beating Amgen’s PCSK9 blockbuster Repatha to market by a month just a year later.

Phil Sharp, Nobel Prize laureate (L), and John Carroll, Endpoints News co-CEO (via Michael Last)

The End­points 11: Fire­side chat with No­bel Prize lau­re­ate Phil Sharp

The following Q&A has been edited for length and clarity.

John Carroll:

We’ve had a chance to talk a little bit before here about some of the things that you’ve done. Just really remarkably, a lot of the things that you’ve done early in your career puts you in the path with some amazing science that has had an absolutely huge impact in terms of what we’re seeing now on drug development and some of the new technologies that are coming out here, and not only the new technologies, but also some of the most remarkable people ever.

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