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.”

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

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