Kamel Khalili (Joseph V. Labolito/Temple University)

Ex­clu­sive: Af­ter four decades, one re­searcher's rad­i­cal HIV cure fi­nal­ly gets its shot

In the down­time be­tween ex­per­i­ments, Kamel Khalili and his men­tor trad­ed their wildest ideas for cur­ing HIV. It was the mid 1980s and Khalili was a post­doc at George Khoury’s Na­tion­al Can­cer In­sti­tute lab, where he stud­ied links be­tween virus­es and tu­mors, then one of the hottest fields in can­cer re­search. But the epi­dem­ic was rag­ing through New York and San Fran­cis­co, mount­ing the largest pub­lic health threat in decades. A cou­ple build­ings over, Robert Gal­lo was se­quenc­ing the virus for the first time. It felt im­pos­si­ble to stay away.

There was one idea Khalili couldn’t stop think­ing about. HIV posed a unique chal­lenge in part be­cause it in­te­grat­ed it­self in­to hu­man DNA, coil­ing away from the body’s de­fens­es. Khalili had spent his grad days tin­ker­ing with one of the ear­li­est tools bi­ol­o­gists in­vent­ed to ma­nip­u­late DNA in­side a liv­ing cell. In fact, the first ex­per­i­ment he was as­signed to when he moved from Tehran to Philadel­phia as a 27-year-old grad­u­ate stu­dent was to take a bac­te­ria-in­fect­ing virus and use it to in­ac­ti­vate a gene in­side E. coli.

He won­dered if he could do the same to the HIV genes in­side a pa­tient’s cells — an idea, he knew, was as lu­di­crous as it was el­e­gant.

“Ob­vi­ous­ly the tool wasn’t there,” Khalili re­calls. The tools they had struck DNA ran­dom­ly, sub­ject­ing the re­cip­i­ent to a scat­ter­shot of ge­net­ic ar­tillery. “You’d kill the pa­tient.”

Then in 2012 came CRISPR, the so-called mol­e­c­u­lar scis­sors that could cut DNA wher­ev­er a re­searcher want­ed. Khalili, who had risen to run a vast neu­ro­science de­part­ment at Tem­ple Uni­ver­si­ty with­out ever giv­ing up on his youth­ful whim, rush­ing to ex­am­ine a new gene edit­ing tool when­ev­er it ap­peared, got to work. With­in a year and a half of Jen­nifer Doud­na and Em­manuelle Char­p­en­tier’s No­bel-win­ning Sci­ence pa­per, he sub­mit­ted a man­u­script to The Pro­ceed­ings of the Na­tion­al Acad­e­my of Sci­ences that would send rip­ples through the HIV field.

He had tak­en CRISPR and used it to ex­cise HIV out of hu­man DNA. When he put it in HIV-in­fect­ed mice a few years lat­er, about a third were cured.

“I’ve been work­ing on HIV for close to 40 years,” says Khalili. Now 69, he has an easy, avun­cu­lar laugh even over Zoom and large ex­pres­sive eye­brows, though col­leagues tell me he can have a far hard­er edge in the lab. “For the first time we re­al­ized a cure was pos­si­ble.”

In No­vem­ber, Khalili gave the first ev­i­dence the ap­proach could work in mon­keys. In­vestors are now get­ting on board. Ex­ci­sion Bio­Ther­a­peu­tics, the com­pa­ny found­ed around Khalili’s work, an­nounced to­day a $50 mil­lion Se­ries A to push the ther­a­py in­to the clin­ic. If it works as in­tend­ed, it could pro­vide a long-sought sin­gle-shot cure for a virus that now in­fects 38 mil­lion peo­ple world­wide and set the stage for a sim­i­lar ap­proach for oth­er chron­ic virus­es, such as her­pes and he­pati­tis B.

In a field al­ready burned count­less times, out­side re­searchers are un­der­stand­ably cau­tious: CRISPR is a pow­er­ful tool, they say, but try­ing to ex­cise all the vi­ral DNA lurk­ing in a pa­tient’s cells is like try­ing to plumb an oil spill; there’s al­ways a bit left, tucked in hard-to-reach places. Still, many were im­pressed he got this far, hav­ing dis­count­ed the ap­proach years be­fore. And they broad­ly agreed that Khalili may have in­vent­ed one of the weapons for the mul­ti-pronged as­sault they think will one day take down the virus.

The first test will come lat­er this year, when a group of pa­tients will be in­ject­ed with Khalili’s ther­a­py and, even­tu­al­ly, tak­en off the an­ti-retro­vi­ral med­i­cines that have kept their in­fec­tions at bay. If the in­fec­tions don’t re­turn, they will owe it to an im­mi­grant sci­en­tist, who flung him­self in­to a cri­sis much of his adopt­ed coun­try ig­nored and for four decades nev­er let go of a brash and maybe even bril­liant idea, even when the tools didn’t ex­ist and the NIH told him it was im­pos­si­ble.

Fy­o­dor Urnov

Skep­ti­cism still runs high, just not as high as when Khalili first start­ed sketch­ing out the idea to friends and col­leagues on nap­kins near­ly a decade ago.

“We have to be very care­ful,” says Fy­o­dor Urnov, a gene edit­ing ex­pert at Cal-Berke­ley who worked on ear­ly HIV gene edit­ing stud­ies. “But I think, over­all, the field can move from hy­po­thet­i­cal to re­al­is­tic op­ti­mism.”

***

Ex­ci­sion isn’t the on­ly com­pa­ny try­ing to ap­ply CRISPR to HIV. Last year CRISPR Ther­a­peu­tics re­ceived a grant from the Bill & Melin­da Gates Foun­da­tion to do ear­ly lab work on a gene ther­a­py that, by IV in­fu­sion, could knock out the re­cep­tors HIV us­es to en­ter cells.

Gene edit­ing ap­proach­es are gain­ing trac­tion in part be­cause the hunt for a cure has reached an im­passe. In the late ’90s and ear­ly 2000s, an­ti-retro­vi­ral drugs brought AIDS un­der con­trol for the first time, sav­ing mil­lions of lives, but they fell short of a panacea. Stop tak­ing your dai­ly pills and the in­fec­tion re­turned. The pills were not with­out side ef­fects, ei­ther, in­clud­ing nau­sea, di­ar­rhea and long-term con­se­quences re­searchers are still doc­u­ment­ing.

In 2008, re­searchers at a Boston AIDS con­fer­ence re­port­ed on the “Berlin pa­tient,” a mid­dle-aged man who was cured of HIV af­ter re­ceiv­ing a bone mar­row trans­plant for leukemia. Doc­tors knew the ther­a­py wasn’t re­mote­ly scal­able. It had near­ly killed the pa­tient, lat­er iden­ti­fied as Tim­o­thy Ray Brown. But it told re­searchers for the first time in three decades of fit­ful progress that a cure was pos­si­ble.

Carl Di­ef­fen­bach

The 12 years since have brought the op­po­site: a se­ries of dead-ends for sci­en­tists’ most promis­ing ap­proach­es.

“We’re in this — I think pur­ga­to­ry is a good way to de­scribe it,” says Carl Di­ef­fen­bach, who runs AIDS re­search at the Na­tion­al In­sti­tute for Al­ler­gy and In­fec­tious Dis­ease. “We need break­throughs.”

De­pend­ing on which HIV re­searcher you ask, they might tell you a cure is like­ly in the next 10 years, or a long shot in the next 40.“We’ve now had 10 years of vig­or­ous ef­forts and it’s proven to be in­cred­i­bly chal­leng­ing,” says Daniel Ku­ritzkes, head of in­fec­tious dis­ease of Boston’s Brigham and Women’s Hos­pi­tal. “It’s pos­si­ble that in 30 years we’ll have some means of achiev­ing a sus­tained re­mis­sion, at least, even if not nec­es­sar­i­ly a cure. But I couldn’t give you odds.”

The prob­lem is the same one that cap­ti­vat­ed Khalili in his NIH days: HIV tucks it­self in­to DNA, form­ing a per­ma­nent reser­voir be­yond the reach of both tra­di­tion­al drugs and the im­mune sys­tem.

Daniel Ku­ritzkes

To get at the reser­voir, sci­en­tists set­tled on two strate­gies that would make Sun Tzu proud: “kick-and-kill,” a way of coax­ing out the hid­den cells and then sub­ject­ing them to a full-on im­mune as­sault;  or “lock and block,” a way of per­ma­nent­ly bury­ing the reser­voir by, for ex­am­ple, screw­ing with the ge­net­ic cir­cuit­ry that al­lows it to trans­late back in­to virus. But no one’s ever had a ma­jor break­through; a 2019 pa­per cast doubt on whether kick-and-kill could ever work.

Gene ther­a­py, al­though gen­er­al­ly talked about for rare dis­ease, has long pro­vid­ed a third route, go­ing back to some of the ear­li­est gene ther­a­py com­pa­nies in the 1990s. The first time gene edit­ing was used in hu­mans was for HIV. In 2008 Carl June, the Uni­ver­si­ty of Penn­syl­va­nia im­mu­nol­o­gist who would lat­er be­come fa­mous for cur­ing can­cer pa­tients with the first CAR-T ther­a­py, ex­tract­ed T cells from HIV pa­tients, used zinc fin­ger nu­cle­as­es to cut out the CCR5 re­cep­tor that HIV lever­ages to en­ter cells, and then reim­plant­ed the T cells.

Lynn Pul­liam

The CCR5 ap­proach has large­ly dom­i­nat­ed gene-based ap­proach­es to HIV, in­clud­ing CRISPR’s new ef­fort, and un­der­stand­ably so. The Berlin pa­tient and, lat­er, the Lon­don pa­tient were cured be­cause they re­ceived bone mar­row trans­plants from peo­ple who nat­u­ral­ly lacked the re­cep­tor. Still, it cur­rent­ly in­volves a stem cell trans­plant, sub­ject­ing large­ly healthy pa­tients to a la­bo­ri­ous and in­ten­sive pro­ce­dure that is not read­i­ly scal­able. And, as more pa­tients re­ceived it over the last decade, one thing be­came clear: They are not, in most cas­es, be­ing cured — adding it to a long list of de­mi-reme­dies.

“They just weren’t work­ing, they weren’t work­ing,’ says Lynn Pul­liam, who runs an HIV lab at the Uni­ver­si­ty of Cal­i­for­nia, San Fran­cis­co. In that en­vi­ron­ment, even ideas as rad­i­cal as Khalili’s felt tryable, how­ev­er im­plau­si­ble many sci­en­tists found it. “It was one of the last tech­niques that some­one had pulled out.”

***

Robert Gal­lo, cen­ter, who helped dis­cov­er the HIV virus while at the NIH in 1984, the year Khalili joined

Click on the im­age to see the full-sized ver­sion

Khalili, born in 1951, grew up in a dif­fer­ent Tehran. Ruled by the Shah, an Amer­i­can-backed dic­ta­tor, it host­ed sci­en­tif­ic con­fer­ences where the West’s top mol­e­c­u­lar bi­ol­o­gists flew in to present and where a teenage Khalili learned about the lat­est ad­vance­ments in a field just be­gin­ning to ac­quire the tools to mess with life’s cen­tral code. When Khalili flew out to the Uni­ver­si­ty of Penn­syl­va­nia to in­ter­view for a grad­u­ate po­si­tion with Joseph Gots, the two sat in his fac­ul­ty of­fice and talked about Per­sian food and Iran­ian his­to­ry. Gots knew the coun­try well.

Khlili ap­plied for a PhD at both Penn and the Uni­ver­si­ty of Mi­a­mi, where he would have be­come a ma­rine bi­ol­o­gist — part of some quixot­ic, save-the-fish dream he still won­ders about. He even vis­it­ed their fa­cil­i­ty. But Penn had the best mol­e­c­u­lar bi­ol­o­gy pro­gram in the coun­try and his wife, a sim­i­lar­ly prodi­gious stu­dent named Shohreh Ami­ni, al­so land­ed a spot there. They ar­rived in 1978 and Gots put him to work in­ac­ti­vat­ing E. coli genes.

The Shah’s gov­ern­ment col­lapsed five months lat­er. Khalili watched the un­rest from his TV set in Philadel­phia, and then the rise of an Is­lam­ic cler­ic as a new dic­ta­tor. “I didn’t like it, and I said that’s not the place I want­ed to do work,” he says. “So I stayed in Philadel­phia.”

He poured him­self in­to his grad­u­ate work, hop­ing that their re­search in gene in­ac­ti­va­tion would chart a path to­ward neu­tral­iz­ing the genes that cause can­cer. He then moved to Khoury’s lab at the Na­tion­al Can­cer In­sti­tute, where he start­ed work­ing on what, be­fore his CRISPR work, he be­come most fa­mous for: how a com­mon in­fec­tion called JC virus can whip and warp cel­lu­lar ma­chin­ery, dri­ving a rare form of brain can­cer.

It was an aus­pi­cious time to join the NCI. The same year, 1984, Robert Gal­lo iso­lat­ed a retro­virus in AIDS pa­tients, giv­ing a source for the mys­te­ri­ous epi­dem­ic that had bro­ken out among gay men and IV drug users. As with Covid-19, sci­en­tists from oth­er dis­ci­plines slow­ly poured in to tack­le the emerg­ing threat. Some of the biggest names in the his­to­ry of vi­rol­o­gy were study­ing it: names like David Ho, Tony Fau­ci, and David Bal­ti­more.

At the same time, stig­ma con­fined the dis­ease to an Amer­i­can mar­gin. And oth­er prob­lems — any prob­lem — seemed more tractable than a fa­tal, rapid­ly mu­tat­ing virus that snakes it­self di­rect­ly in­to hu­man DNA. “A lot of peo­ple didn’t even want to touch it,” Pul­liam re­calls.

Khalili tweaked his re­search to cov­er the cri­sis, study­ing how JC virus in­ter­acts with HIV and how HIV af­fects the ner­vous sys­tem. He patent­ed small mol­e­cules to block the virus from in­te­grat­ing in­to DNA. “I was al­ways think­ing about how I could get in­to HIV,” he says. “It was a much big­ger prob­lem.”

He re­turned to Tehran on­ly once, ac­cept­ing an in­vi­ta­tion in the ear­ly ’90s to give a se­ries of work­shops on gene trans­fer at the Pas­teur In­sti­tute of Iran. But the city had changed. In­stead, he fell in love with Philadel­phia, go­ing to Thomas Jef­fer­son Uni­ver­si­ty af­ter the NCI and then start­ing his own lab at Tem­ple.

He made friends quick in his adopt­ed coun­try, im­press­ing oth­er sci­en­tists with a quick mind and an ea­ger­ness to share ideas that oth­ers jeal­ous­ly guard­ed. Joc­u­lar yet ur­bane, he in­vit­ed fel­low con­fer­ence at­ten­dees to sin­gle-malt scotch tast­ings in Ed­in­burgh or to sip limon­cel­lo in Italy. And when out-of-town col­leagues stopped by Philly, he’d whisk them around to his fa­vorite Ital­ian restau­rants. Af­ter the Ea­gles fi­nal­ly made the Su­per Bowl in 2018, he flew to Min­neapo­lis to watch them win in per­son.

He had a hard­er edge in the lab, col­leagues say. He kept his of­fice metic­u­lous­ly clean. Un­til Covid-19 in­ter­rupt­ed, he held hour-long re­view meet­ings on Sat­ur­days, oc­ca­sion­al­ly frus­trat­ing grad stu­dents. You could screw up the ex­per­i­ment but he’d grow frus­trat­ed if you didn’t have an ex­pla­na­tion, or didn’t fol­low his in­struc­tions, or didn’t keep up with the lit­er­a­ture. It wasn’t a place for peo­ple who need­ed a pat on the head every time they did well.

Rafal Kamin­s­ki

“You al­ways had di­rec­tion and you al­ways know what you’re do­ing,” says Rafal Kamin­s­ki, who worked with Khalili for 16 years as a grad­u­ate stu­dent and pro­fes­sor. “The on­ly prob­lem is he al­ways want­ed so much.”

It worked, though. Bri­an Wig­dahl, chair of mi­cro­bi­ol­o­gy and im­munol­o­gy at Drex­el Uni­ver­si­ty, says he built one of the best neu­ro­science de­part­ments in the coun­try, de­spite no for­mal train­ing in neu­ro­science. Kamin­s­ki, who joined with a de­gree from a promi­nent Pol­ish uni­ver­si­ty but lit­tle lab ex­pe­ri­ence, cred­its Khalili with teach­ing him every­thing he knows. He be­came a “lu­mi­nary” in the field, says Steven Ja­cob­son, a neu­rovi­rol­o­gist at NIH, found­ing its jour­nal and in­ter­na­tion­al so­ci­ety.

Bri­an Wig­dahl

Be­yond neu­rovi­rol­o­gy, too. His in­ter­ests were poly­glot, and he added col­lab­o­ra­tors as he chased new is­sues. “He will move in­to new ar­eas and you don’t even know he’s there,” Wig­dahl says. “He jumps on things faster than any­one I know.”

That in­clud­ed gene ed­i­tors. In the 1990s, re­searchers start­ed en­gi­neer­ing new DNA-snip­ing en­zymes called zinc fin­ger nu­cle­as­es and TAL­ENs that of­fered im­prove­ments on the tools they had in the ’80s. Khalili rarely spoke about it, but he ex­am­ined each for po­ten­tial in HIV, be­fore re­ject­ing them as too cum­ber­some or im­pre­cise.

Then in Oc­to­ber 2012 when Kamin­s­ki was about to fly back to Poland to de­fend his PhD the­sis, Khalili pulled him out­side and told him he had a spe­cial project for him when he re­turned. It was three months af­ter Doud­na and Char­p­en­tier’s pa­per but be­fore Feng Zhang would show CRISPR could ed­it hu­man cells.

“I looked at him like oh my God, what is go­ing to hap­pen now?” Kamin­s­ki says. “But I said, OK.”

***

In the months be­fore PNAS pub­lished his pa­per, Khalili couldn’t stop talk­ing about it. Wig­dahl said he saw him sketch it for col­leagues on nap­kins: a whir of en­zymes, RNA and hu­man vi­ral DNA. Pul­liam re­mem­bered him be­ing school­boy-gid­dy over mar­ti­nis one night, com­par­ing it to a ground­break­ing pa­per she had pub­lished in the ’80s, show­ing AIDS de­men­tia wasn’t caused by the virus it­self.

The pa­per pub­lished in Ju­ly, show­ing for the first time that a gene edit­ing tool could erad­i­cate vi­ral DNA, al­so known as la­tent HIV or provirus, from cell cul­tures. In fact, it was one of the first times in three decades of AIDS re­search that any­one had been able to get at the reser­voir at all.

(From left to right). 1. In all pa­tients, HIV in­te­grates in­to hu­man DNA, form­ing a per­ma­nent reser­voir be­yond the reach of drugs or the im­mune sys­tem. 2. In Khalili’s ap­proach, guide RNAs lead DNA-cut­ting Cas9 en­zymes to key sites on the vi­ral DNA. 3.  The Cas9 en­zymes cut slice the HIV DNA, which falls away 4. The DNA re­pairs it­self, form­ing a healthy strand, with most or all of the HIV re­moved. (Il­lus­tra­tion – Adri­ana Mari­cari, End­points News)

Click on the im­age to see the full-sized ver­sion

CRISPR con­sists of es­sen­tial­ly two tools: a DNA-cut­ting en­zyme called Cas and a guide RNA that tells Cas where to cut. When Doud­na, Char­p­en­tier and Zhang first showed the sys­tem, re­verse-en­gi­neered from bac­te­ria, could ed­it hu­man DNA, spec­u­la­tion cen­tered around whether re­searchers could now re­pair genes be­hind rare and fa­tal dis­or­ders like cys­tic fi­bro­sis or Duchenne mus­cu­lar dy­s­tro­phy. Fix­ing a gene, though, re­quires a third tool, one sci­en­tists are still strug­gling to mas­ter: a re­place­ment strand of DNA for the cell to put at the site of the break.

It’s much eas­i­er to sim­ply crip­ple a gene. Every CRISPR-based ther­a­py now in the clin­ic us­es this ap­proach, in­clud­ing Ver­tex’s sick­le cell treat­ment. It’s what made HIV an at­trac­tive op­tion.

In the 3 bil­lion-let­ter chain of hu­man DNA, la­tent HIV sits swad­dled be­tween two 634-let­ter, repet­i­tive strands that con­tain the in­struc­tions for trans­lat­ing HIV DNA back in­to the virus. Khalili’s team used soft­ware to iden­ti­fy crit­i­cal sec­tions of these so-called long-ter­mi­nal re­peats. They then made sure tar­get­ing these sec­tions wouldn’t in­ter­fere with healthy gene ex­pres­sion.

HIV shapeshifts eas­i­ly, al­low­ing it to over­come in­di­vid­ual an­tivi­rals and, po­ten­tial­ly, in­di­vid­ual cuts to its genome. To avoid that risk, Khalili’s team de­signed mul­ti­ple dif­fer­ent guide RNAs and de­cid­ed to try and slice en­tire chunks out of the provirus. They suc­cess­ful­ly cut a small por­tion, and “then we got a lit­tle bit more am­bi­tious,” Khalili says. They cut out of an im­mune cell a com­plete, 9,709-let­ter stretch of HIV DNA. In a pa­tient, it would amount to surgery by IV, slic­ing DNA out of cells like tu­mor from tis­sue.

Howard Gen­del­man

“That got every­one in­ter­est­ed,” says Howard Gen­del­man, who runs his own HIV and neu­rovi­rol­o­gy lab at the Uni­ver­si­ty of Ne­bras­ka Med­ical Cen­ter. Gen­del­man and Khalili had been ri­vals for decades, two ti­tans of a small field who crossed paths for the first time at the NCI in 1987.

“We were at the same lev­el, at the same time, at the same age, study­ing the same very thing,” he says. “Two poles of the same po­lar­i­ty re­pel.”

Gen­del­man, though, had de­vel­oped one of the world’s best mouse mod­els for HIV, the next log­i­cal place for Khalili to test his mod­el. And af­ter the in­ter­ces­sion of an­oth­er well-known HIV re­searcher — who called Gen­del­man at his daugh­ter’s en­gage­ment par­ty and screamed at him for sev­er­al min­utes to get over him­self and work with Khalili be­cause the two had com­pli­men­ta­ry tech­nol­o­gy — they start­ed col­lab­o­rat­ing.

They wrote a grant pro­pos­al, as they had each suc­cess­ful­ly done hun­dreds of times in their ca­reers. But an NIH com­mit­tee re­ject­ed their ap­pli­ca­tion.

“They thought it was ba­si­cal­ly im­pos­si­ble,” Khalili says.

***

Khalili and Tri­cia Bur­do, who de­signed the stud­ies show­ing the ap­proach could work in mon­keys. (Joseph V. Laboli­to/Tem­ple Uni­ver­si­ty)

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Avin­dra Nath

Khalili was not the first re­searcher to pro­pose gene edit­ing HIV. A team at Ky­oto Uni­ver­si­ty pub­lished a study cut­ting la­tent HIV with CRISPR near­ly a year be­fore Khalili did, al­though ul­ti­mate­ly with much less suc­cess. Ref­er­ences in the lit­er­a­ture go back decades. “The idea was out there,” says Avin­dra Nath, head of neu­rovi­rol­o­gy at NIH. “No one thought it would work.”

That in­clud­ed mem­bers of Khalili’s own team. Jonathan Karn, a Case West­ern AIDS re­searcher whom Khalili en­list­ed for his ex­per­tise in mea­sur­ing the HIV reser­voir, re­mem­bers hear­ing the pitch and telling Khalili that he thought it had no chance of work­ing. Khalili told him that’s why he want­ed Karn on the team.

Jonathan Karn

There were nu­mer­ous sci­en­tif­ic and tech­ni­cal hur­dles to CRISPRing HIV, most of which the PNAS pa­per didn’t be­gin to scratch. Even now, with ear­ly mon­key da­ta, sev­er­al re­main un­ad­dressed.

Karn was par­tic­u­lar­ly con­cerned with de­liv­ery. Gene ther­a­pies are gen­er­al­ly in hol­lowed out virus­es, called a vec­tor. Re­searchers, though, on­ly in­ject­ed CRISPR di­rect­ly in­to hu­mans for the first time last year, when Ed­i­tas launched a tri­al in the eye, a large­ly self-con­tained or­gan that has long been one of the eas­i­est places to do gene ther­a­py. And it was un­clear un­til re­cent­ly whether AAV9, the hol­lowed-out virus most CRISPR com­pa­nies use to de­liv­er their ther­a­pies, could go to T cells, home to most of the HIV reser­voir.

Hit­ting T cells, though, is just the first step. In an av­er­age pa­tient, on­ly about 40 in every mil­lion T cells con­tain la­tent HIV. Oth­er cell types with la­tent HIV are scat­tered through­out the body. And HIV does not in­te­grate in­to the same spot in every cell.

Carl June

Khalili and Gen­del­man had to hit bullseyes with­in bullseyes. Still, when they tried it in mice, cob­bling to­geth­er fund­ing from oth­er sources, they were able to ex­cise enough HIV to pre­vent the in­fec­tion from re­turn­ing. NIH fund­ing fol­lowed and in No­vem­ber, they showed that they could wipe out be­tween 38% and 95% of la­tent SIV — the simi­an equiv­a­lent of HIV — in three mon­keys.

“It’s find­ing the nee­dle in the haystack and then cut­ting it out,” says Carl June, the im­mu­nol­o­gist who pi­o­neered the CCR5-knock­out ap­proach. “It’s amaz­ing they could do it all.”

***

June is im­pressed with the ap­proach, but he doesn’t be­lieve it will bring a cure. He’s not alone. Sev­er­al re­searchers tell me that Ex­ci­sion may be able to knock out some, maybe even most, of the reser­voir. But if they can’t get all of it, then the in­fec­tion will sim­ply come roar­ing back. And like near­ly all cur­rent gene ther­a­pies, it can’t be dosed twice: You on­ly have one shot to make it work.

Sharon Lewin

“It de­pends on how ef­fec­tive it is in elim­i­nat­ing every in­fect­ed cell,” says Sharon Lewin, di­rec­tor of the Pe­ter Do­her­ty In­sti­tute for In­fec­tion and Im­mu­ni­ty in Mel­bourne. “And that would be a big ask.”

No one, though, has ever made a dent in the reser­voir. Per­haps you need to de­plete it en­tire­ly; per­haps you just have to knock it down enough. Two out of the sev­en hu­man­ized mice they treat­ed in their study ap­peared to be cured, even though they hadn’t ex­cised 100% of provi­ral DNA. And Khalili point­ed out that the Berlin pa­tient still had la­tent HIV, just not enough that his im­mune sys­tem couldn’t con­trol it. “Do you re­al­ly need to hit every sin­gle cell?” he says.

Khalili has been ig­nor­ing crit­ics for a decade, but he’s still hedg­ing his bets. In the past eight years, his CRISPR work has gone from a lit­tle dis­cussed project be­tween him, Kamin­s­ki and a post­doc to one that en­com­pass­es most of Khalili’s lab and grants, with 10 grad­u­ate stu­dents or lab work­ers, a hand­ful of se­nior in­ves­ti­ga­tors and uni­ver­si­ties across the coun­try. Khalili’s lat­est grant pro­pos­al is to team with out­side ex­perts on an ap­proach both June and Lewin said was promis­ing: com­bin­ing their tech­nol­o­gy with an im­mune-boost­ing mol­e­cule that would help the body take care of the cells CRISPR doesn’t reach.

It’s part of a group of tech­nolo­gies June says are bring­ing a cure with­in reach. Just a year younger than Khalili, June has been study­ing HIV for near­ly as long and he says the prob­lem has changed in re­cent years: from de­vel­op­ing new tools to im­ple­ment­ing cur­rent ones. His CCR5-knock­out ap­proach, for ex­am­ple, still holds sig­nif­i­cant promise when com­bined with im­mune boost­ers or vac­cines, par­tic­u­lar­ly if re­searchers can fig­ure out a way of do­ing the cell trans­plant with­out chemother­a­py.

Di­ef­fen­bach, the NI­AID HIV chief, spec­u­lat­ed you could com­bine ei­ther ap­proach with a vac­cine Vir just put in­to Phase I, which is meant to train T cells to at­tack the virus.

“The fu­ture will re­quire mul­ti­ple hits,” he says. “It won’t ever be one thing.”

Im­ple­ment­ing won’t be easy, though. Be­cause most pa­tients have their in­fec­tion un­der con­trol, the safe­ty bar to test a new treat­ment on hu­mans is high­er than it is for most can­cers or rare dis­eases. Ex­ci­sion Bio, for ex­am­ple, has the best chance of hit­ting all la­tent cells by us­ing high dos­es of the AAV9 vec­tor that car­ries their ther­a­py, but high dos­es have shown dan­ger­ous side ef­fects in a few rare dis­ease gene ther­a­py tri­als. They’ll in­stead launch Phase I this year with a low­er dose than Khalili used in his mon­key stud­ies, though they could still raise the amount in fu­ture tri­als.

Suc­cess would bring its own hur­dles. AAV can’t yet be man­u­fac­tured at any­where near the scale to reach the 38 mil­lion peo­ple with HIV world­wide, so a cure would ini­tial­ly fur­ther al­ready un­equal ac­cess to med­i­cines. Still, June said he was con­fi­dent that com­pa­nies would solve that ques­tion for both Khalili’s ap­proach and his own cell ther­a­py ap­proach. Phar­ma com­pa­nies have too much in­cen­tive.

“Those will hap­pen with­in a decade,” June says. “There’s bil­lions of dol­lars be­ing in­vest­ed in these is­sues be­cause of gene ther­a­py and cell ther­a­py for can­cer. That didn’t ex­ist years ago.”

***

Steven Deeks

Even if it works not every­one would be el­i­gi­ble. Khalili on­ly showed CRISPR can work on pa­tients who al­ready have their HIV un­der con­trol, leav­ing out the pa­tients most in need of a cure. “It’s a big eth­i­cal dilem­ma,” says Steven Deeks, an HIV re­searcher at UCSF.

Deeks, who signed a col­lab­o­ra­tion with Ex­ci­sion short­ly af­ter our con­ver­sa­tion, rat­tled off nu­mer­ous rea­sons why Ex­ci­sion could fail, in­clud­ing the po­ten­tial to dis­rupt hu­man DNA along­side HIV DNA, cau­tion­ing that they would have to move ex­treme­ly slow. Still, he said, it could help mil­lions of pa­tients who strug­gle to take dai­ly meds or face stig­ma when do­ing so. And it would of­fer an ad­van­tage over oth­er ap­proach­es that try for a “func­tion­al cure,” leav­ing HIV in the body but in­ert.

“What every­one wants is a com­plete cure, they don’t want to have any of the virus left,” Deeks says. “This is one of the most promis­ing ways of achiev­ing that ul­ti­mate goal.”

It would be a mas­sive achieve­ment, one that Khalili and vir­tu­al­ly every HIV re­searcher have been dream­ing of for decades. But one that a few now say is with­in reach.

Fy­o­dor Urnov, the Berke­ley gene edit­ing ex­pert, of­fered a space anal­o­gy and a lit­mus test for the fea­si­bil­i­ty of any sci­en­tif­ic en­deav­or: What tools al­ready ex­ist and what have to be in­vent­ed?

“We want to go to Mars? Well kind of the pieces are there, we just need to do it,” he says. “We want to go Al­pha Cen­tau­ri? It’s a fun­da­men­tal­ly dif­fer­ent tech­no­log­i­cal chal­lenge where some things are just cur­rent­ly im­pos­si­ble.”

An HIV cure, he says, is now like reach­ing Mars. And Khalili, de­spite all the fail­ures of the last four decades, is con­fi­dent he can be the next Neil Arm­strong. What are the odds he’s right?

“I don’t know, I think it’s pos­si­ble,” says Lynn Pul­liam. “Yeah, I think it’s pos­si­ble, I do. I think it’s pos­si­ble.”

2023 Spot­light on the Fu­ture of Drug De­vel­op­ment for Small and Mid-Sized Biotechs

In the context of today’s global economic environment, there is an increasing need to work smarter, faster and leaner across all facets of the life sciences industry.  This is particularly true for small and mid-sized biotech companies, many of which are facing declining valuations and competing for increasingly limited funding to propel their science forward.  It is important to recognize that within this framework, many of these smaller companies already find themselves resource-challenged to design and manage clinical studies themselves because they don’t have large teams or in-house experts in navigating the various aspects of the drug development journey. This can be particularly challenging for the most complex and difficult to treat diseases where no previous pathway exists and patients are urgently awaiting breakthroughs.

Dipal Doshi, Entrada Therapeutics CEO

Ver­tex just found the next big ‘trans­for­ma­tive’ thing for the pipeline — at a biotech just down the street

Back in the summer of 2019, when I was covering Vertex’s executive chairman Jeff Leiden’s plans for the pipeline, I picked up on a distinct focus on myotonic dystrophy Type I, or DM1 — one of what Leiden called “two diseases (with DMD) we’re interested in and we continue to look for those assets.”

Today, Leiden’s successor at the helm of Vertex, CEO Reshma Kewalramani, is plunking down $250 million in cash to go the extra mile on DM1. The lion’s share of that is for the upfront, with a small reserve for equity in a deal that lines Vertex up with a neighbor in Seaport that has been rather quietly going at both of Vertex’s early disease targets with preclinical assets.

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WIB22: Am­ber Salz­man had few op­tions when her son was di­ag­nosed with a rare ge­net­ic dis­ease. So she cre­at­ed a bet­ter one

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

Amber Salzman’s life changed on a cold, damp day in Paris over tiny plastic cups of lukewarm tea.

She was meeting with Patrick Aubourg, a French neurologist studying adrenoleukodystrophy, or ALD, a rare genetic condition that causes rapid neurological decline in young boys. It’s a sinister disease that often leads to disability or death within just a few years. Salzman’s nephew was diagnosed at just 6 or 7 years old, and died at the age of 12.

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WIB22: Lead­ing NK cell re­searcher re­flects on roots in Iran, the UK and Texas

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

In a small but widely-cited 11-person study published in NEJM in 2020, seven patients saw signs of their cancer completely go away after getting a new therapy made from natural killer cells. The study was one of the earliest to provide clinical proof that the experimental treatment method had promise.

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WIB22: Chas­ing af­ter ever-evolv­ing sci­ence takes a drug hunter across the pond

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

Like many scientists, Fiona Marshall would tell you that she loved the natural world growing up — going to look at crabs running around the beach near her childhood home, pondering about the tides. But one thing about biology, in particular, stood out: It was constantly changing, and changing very quickly.

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Ahead of ad­comm, FDA rais­es un­cer­tain­ties on ben­e­fit-risk pro­file of Cy­to­ki­net­ic­s' po­ten­tial heart drug

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will meet next Tuesday to discuss whether Cytokinetics’ potential heart drug can safely reduce the risk of cardiovascular death and heart failure in patients with symptomatic chronic heart failure with reduced ejection fraction.

The drug, known as omecamtiv mecarbil and in development for more than 15 years, has seen mixed results, with a first Phase III readout from November 2020 hitting the primary endpoint of reducing the odds of hospitalization or other urgent care for heart failure by 8%. But it also missed a key secondary endpoint analysts had pegged as key to breaking into the market.

Ab­b­Vie slapped with age dis­crim­i­na­tion law­suit, fol­low­ing oth­er phar­mas

Add AbbVie to the list of pharma companies currently facing age discrimination allegations.

Pennsylvania resident Thomas Hesch filed suit against AbbVie on Wednesday, accusing the company of passing him over for promotions in favor of younger candidates.

Despite 30 years of pharma experience, “Hesch has consistently seen younger, less qualified employees promoted over him,” the complaint states.

Rami Elghandour, Arcellx CEO

Up­dat­ed: Gilead, Ar­cel­lx team up on an­ti-BC­MA CAR-T as biotech touts a 100% re­sponse rate at #ASH22

Gilead and Kite are plunking down big cash to get into the anti-BCMA CAR-T game.

The pair will shell out $225 million in cash upfront and $100 million in equity to Arcellx, Kite announced Friday morning, to develop the biotech’s lead CAR-T program together. Kite will handle commercialization and co-development with Arcellx, and profits in the US will be split 50-50.

Concurrent with the deal, Arcellx revealed its latest cut of data for the program known as CART-ddBCMA, ahead of a full presentation at this weekend’s ASH conference — a 100% response rate among patients getting the therapy. Investors jumped at the dual announcements, sending Arcellx shares $ACLX up more than 25% in Friday’s morning session.

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Stephen Squinto, Gennao Bio chairman

Scoop: Stephen Squin­to’s Yale spin­out is rais­ing a Se­ries B for ge­net­ic med­i­cines

The nucleic acid therapeutics at Stephen Squinto’s Yale-originated biotech are en route to a $40 million R&D payday.

After a Series A of that size in the spring of 2021, Hopewell, NJ-based Gennao Bio is closing on a round of the same amount, Endpoints News has learned. A Series B is in the works, according to an investor’s post on LinkedIn and as confirmed by a spokesperson. An SEC filing on Thursday outlines $15 million in equity sold thus far in the round.

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