Are we clos­er than we think to per­son­al­ized ge­net­ic med­i­cine?

When gene edit­ing ex­plod­ed on­to the scene over three decades ago, it brought pre­vi­ous­ly in­con­ceiv­able dis­ease treat­ment and po­ten­tial­ly cu­ra­tive ther­a­pies in­to view. To­day, gene edit­ing re­mains one of the most grip­ping top­ics in bio­phar­ma — and a re­cent wave of part­ner­ships may move the in­dus­try even clos­er to broad, cu­ra­tive treat­ment for ge­net­ic dis­ease.

Dis­cov­er­ies across the nat­ur­al en­vi­ron­ment de­riv­ing in vi­vo and ex vi­vo biotech­nolo­gies have ush­ered a flood­gate of de­vel­op­ment pos­si­bil­i­ties. With gi­ants like Bay­er, Mod­er­na, Ver­tex and oth­ers sig­nal­ing that gene edit­ing will be a key dri­ver of their fu­ture pipelines, how will the in­dus­try lever­age this new fron­tier of ge­nom­ic tech­nol­o­gy?

A pan­el spon­sored by Metageno­mi and mod­er­at­ed by End­points News at the 2022 BIO In­ter­na­tion­al Con­ven­tion con­vened an in­te­grat­ed group of thought lead­ers, lead­ing sci­en­tists and in­vestors to dis­cuss the best prac­tices to de­vel­op safe, ef­fi­ca­cious gene ther­a­pies for the fu­ture. Here we cap­ture in­sights from each per­spec­tive and pan­elist.

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Ex­pand­ing the gene edit­ing tool­box through metage­nomics

Most ge­net­ic mod­i­fi­ca­tion tri­als to­day em­ploy the rev­o­lu­tion­ary CRISPR-Cas9 method of DNA cut­ting, whose cre­ators were award­ed the No­bel Prize in chem­istry just two years ago. While CRISPR-Cas9 tech­niques may pro­vide a chance to treat some gene-re­lat­ed dis­eases, more in­no­va­tion is need­ed to un­lock the full po­ten­tial of gene edit­ing. With that goal in mind, Metageno­mi is lead­ing a new wave of star­tups look­ing to cre­ate pow­er­ful next-gen­er­a­tion gene edit­ing sys­tems that can en­able and ac­cel­er­ate the dis­cov­ery and de­vel­op­ment of cus­tomized gene edit­ing ther­a­pies across a wider range of ge­net­ic dis­eases and tis­sues.

Backed by $300 mil­lion, Metageno­mi is comb­ing the world’s nat­ur­al mi­cro­bial en­vi­ron­ment to dis­cov­er break­through gene edit­ing sys­tems ca­pa­ble of edit­ing DNA more pre­cise­ly than cur­rent tech­nol­o­gy can. The sci­ence be­hind the com­pa­ny is metage­nomics, which ex­am­ines the ge­nealog­i­cal com­po­si­tion of mi­crobes from rich, nat­ur­al en­vi­ron­ments such as hot springs, wet­lands and salt flats. It’s a sci­ence that was pi­o­neered by Metageno­mi’s CEO and founder, Bri­an C. Thomas, who spent two decades ded­i­cat­ed to sci­en­tif­ic re­search at UC Berke­ley.

“Us­ing metage­nomics, we’re tap­ping in­to four bil­lion years of mi­cro­bial evo­lu­tion, and the an­swers are there,” said Thomas. “We haven’t had to spend sig­nif­i­cant amounts of time in the lab en­gi­neer­ing these en­zymes in or­der to at­tain the high lev­els of ac­tiv­i­ty that they’re able to hit, be­cause they’ve been op­ti­mized nat­u­ral­ly.”

The com­pa­ny is rapid­ly build­ing the world’s largest, most di­verse tool­box of both CRISPR and non-CRISPR-based gene edit­ing sys­tems through its pro­pri­etary dis­cov­ery and analy­sis en­gine. This ap­proach re­cov­ers DNA from nat­ur­al sam­ples and us­es ad­vanced AI-based cloud com­put­ing to re­veal nov­el cel­lu­lar ma­chin­ery from pre­vi­ous­ly un­stud­ied or­gan­isms that can be op­ti­mized for ther­a­peu­tic ap­pli­ca­tions. Hav­ing a wider se­lec­tion of mod­u­lar tools en­ables sci­en­tists and health­care providers to tar­get ag­gres­sive can­cers, rare dis­eases and oth­er com­plex­i­ties as they seek to make a dif­fer­ence for pa­tients.

Solv­ing ge­net­ic edit­ing chal­lenges

So far Metageno­mi has iden­ti­fied thou­sands of nov­el en­zymes, many of which are ul­tra-small and dis­play unique char­ac­ter­is­tics for en­hanced gene edit­ing ap­pli­ca­tions. Com­pared to cur­rent edit­ing sys­tems, which are based on a few, large en­zymes with tar­get­ing and de­liv­ery is­sues, Metageno­mi sys­tems of­fer flex­i­bil­i­ty. This broad en­zyme di­ver­si­ty and small­er size en­ables greater ef­fi­cien­cy, speci­fici­ty and genome tar­getabil­i­ty, re­sult­ing in en­hanced pa­tient safe­ty.

“[As] we start­ed our sur­vey in the nat­ur­al en­vi­ron­ment of these unique nu­cle­as­es, we tried to find char­ac­ter­is­tics that would re­al­ly be ben­e­fi­cial with cur­rent de­liv­ery ca­pa­bil­i­ties,” said Thomas. He not­ed that the com­pa­ny is still ex­plor­ing the bio­chem­i­cal prop­er­ties of its unique nu­cle­as­es, in­clud­ing greater sta­bil­i­ty and re­silience due to their ori­gins in ex­treme en­vi­ron­ments, where pH and tem­per­a­ture, for ex­am­ple, are wild­ly atyp­i­cal.

The com­pa­ny’s tool­box is cur­rent­ly weight­ed to­ward CRISPR-based sys­tems but is ex­pand­ing to in­clude tar­get­ed in­te­gra­tion of large DNA frag­ments, base edit­ing and oth­er types of gene edit­ing tools.

Pro­pelling in vi­vo and ex vi­vo ther­a­pies through part­ner­ships

Metageno­mi’s pipeline fo­cus­es on de­ploy­ing its whol­ly-owned di­verse tool­box in both in vi­vo and ex vi­vo ap­pli­ca­tions. “As we start­ed to de­vel­op these tools from the nat­ur­al en­vi­ron­ment, we re­al­ized they had char­ac­ter­is­tics and prop­er­ties that could make them unique in ei­ther of those set­tings,” not­ed Thomas. “From a busi­ness point of view, we’ve re­al­ly fo­cused on a part­ner­ship strat­e­gy around lever­ag­ing both of these tech­nol­o­gy ap­pli­ca­tions.”  In ad­di­tion to en­abling part­ners, Metageno­mi al­so has a whol­ly-owned pipeline of next-gen­er­a­tion ther­a­pies de­vel­oped us­ing the com­pa­ny’s nov­el tech­nolo­gies.

Mod­er­na re­al­ized a part­ner­ship with Metageno­mi — which was an­nounced last year — could help dif­fer­en­ti­ate it as an in vi­vo mar­ket leader in the fu­ture, in­clud­ing through ge­net­ic sys­tem re­pro­gram­ming. The re­search col­lab­o­ra­tion will com­bine Metageno­mi’s gene edit­ing sys­tems with Mod­er­na’s mR­NA tech­nolo­gies to de­vel­op in­no­v­a­tive in vi­vo gene edit­ing ther­a­peu­tics tar­get­ing var­i­ous ge­net­ic dis­eases.

“When work­ing with part­ners like Metageno­mi, we can ac­tu­al­ly cre­ate the next gen­er­a­tion of func­tion­al ge­nom­ic fac­tors that com­bine mR­NA tech­nol­o­gy and the pow­ers of chain man­u­fac­tur­ing,” ex­plained Er­ic Huang, Mod­er­na Ge­nomics’ chief sci­en­tif­ic of­fi­cer. “That’s our blue-sky am­bi­tion and goal … com­bin­ing that knowhow, the fu­ture tech­nol­o­gy gen­er­a­tion, as well as Mod­er­na’s man­u­fac­tur­ing prowess, to re­al­ly make per­son­al­ized ge­net­ic med­i­cine in­to re­al­i­ty” in years to come.

The Metageno­mi team is al­so “ex­cit­ed about the fact that in the ex vi­vo cell ther­a­py space, where the gene edit­ing com­po­nent is a tool to cre­ate a more im­pact­ful and pow­er­ful cell prod­uct, there’s a lot of room for de­vel­op­ment,” shared Thomas.

In fact, the com­pa­ny just an­nounced a part­ner­ship with start­up Affi­ni-T Ther­a­peu­tics to ad­vance next-gen­er­a­tion ex vi­vo T-cell re­cep­tor ther­a­pies — or TCR — for pa­tients with sol­id tu­mors. The work will tar­get core onco­genic dri­vers us­ing Metageno­mi’s pro­pri­etary gene edit­ing sys­tems to pro­mote sus­tained clin­i­cal out­comes for can­cer pa­tients. “Sol­id tu­mors are re­al­ly the next fron­tier in on­col­o­gy,” not­ed Aude Cha­puis, co-founder of Affi­ni-T, as­so­ciate pro­fes­sor at the Fred Hutchin­son Can­cer Cen­ter and a sci­en­tif­ic ad­vi­sor to Metageno­mi. “We’re in­ter­est­ed in TCR tech­nol­o­gy be­cause it is able to tar­get in­tra­cel­lu­lar anti­gens … [so] we can re­al­ly broad­en the num­ber of pro­teins that we’re tar­get­ing,” she said. “Ul­ti­mate­ly, the non-vi­ral gene edit­ing is go­ing to be ex­treme­ly valu­able for the TCR field in par­tic­u­lar.”

Affi­ni-T aims to per­form mul­ti­ple ge­net­ic ed­its of vary­ing com­bi­na­tions across pro­teins, an en­deav­or fraught with chal­lenges, Cha­puis ex­plained. But Metageno­mi’s tool­box of­fers promise for edit­ing ef­fi­cien­cy and tar­get­ing: “I think Metageno­mi has so many en­zymes, so many pos­si­bil­i­ties, so that will help us choose the right ones to be able to achieve the goals,” she said. Thomas con­curred, adding that Metageno­mi is, “very pleased to see that our most char­ac­ter­ized sys­tems are at­tain­ing very high lev­els of ef­fi­cien­cy across mul­ti­ple loci at once.”

Jür­gen Eck­hardt, head of Leaps by Bay­er, the phar­ma­ceu­ti­cal gi­ant’s ear­ly-stage in­vest­ment arm, counts Metageno­mi and Affi­ni-T with­in its port­fo­lio. Both com­pa­nies sat­is­fied the in­vestor’s key ques­tions: “Is this a big un­met med­ical need? Is this some­thing where we see huge po­ten­tial to make a step change? Is this some­thing where we see huge po­ten­tial to go from ther­a­py to cure?” he said. Eck­hardt be­lieves we are in the very ear­ly days of gene edit­ing.“There are thou­sands, hun­dreds of thou­sands, mil­lions more, po­ten­tial­ly [en­zyme nu­cle­as­es to be dis­cov­ered]…. That’s what led us to make an in­vest­ment in Metageno­mi.”

Oth­er in­vestors are sim­i­lar­ly in­ter­est­ed in tap­ping in­to the com­pa­ny’s dis­cov­ery en­gine to probe its pos­si­bil­i­ties. Metageno­mi’s dis­cov­ery plat­form was a dri­ving fac­tor in the in­vestor com­mit­ment for their over­sub­scribed Se­ries B, which closed with $175 mil­lion in fund­ing ear­li­er this year.

Mit­i­gat­ing risk: a crit­i­cal pri­or­i­ty

With an eye to­ward the clin­ic, pan­elists not­ed the im­por­tance of con­tin­ued vig­i­lance in mon­i­tor­ing and mit­i­gat­ing the risk as­so­ci­at­ed with gene edit­ing. Draft FDA guid­ance re­leased in March calls for care­ful mon­i­tor­ing of genome edit­ing risks, such as un­in­tend­ed con­se­quences and un­known long-term ef­fects of on- and off-tar­get edit­ing. The agency rec­om­mends at least 15 years of long-term fol­low-up af­ter clin­i­cal tri­als of gene edit­ing treat­ments.

Gene ther­a­py com­pa­nies want to avoid the fate of Al­lo­gene, which was tem­porar­i­ly forced to sus­pend clin­i­cal op­er­a­tions un­til in­ves­ti­ga­tors con­clud­ed there was no con­nec­tion be­tween the com­pa­ny’s ther­a­py and chro­mo­so­mal changes de­tect­ed in a pa­tient. Strong com­mu­ni­ca­tion with reg­u­la­to­ry agen­cies and care­ful at­ten­tion to pre­clin­i­cal da­ta are crit­i­cal, es­pe­cial­ly since pre­clin­i­cal false pos­i­tives and false neg­a­tives can mud­dy the trans­la­tion to the clin­i­cal set­ting, not­ed Will Dere, a Metageno­mi board mem­ber, pro­fes­sor of in­ter­nal med­i­cine and as­so­ciate vice pres­i­dent of re­search at the Uni­ver­si­ty of Utah Health Sci­ences Cen­ter.

Giv­en the in­fan­cy of the field, Thomas em­pha­sized, sci­en­tists are just be­gin­ning to un­der­stand off-tar­get ac­tiv­i­ties and how they cul­mi­nate in prob­lem­at­ic out­comes. Re­cent­ly an­nounced ex vi­vo ther­a­pies may in­volve as many as a dozen dif­fer­ent ed­its with­in a sin­gle prod­uct — but an en­zyme that is high­ly tar­get­ed and opens a genome at a sin­gle lo­ca­tion at a time could mit­i­gate the risk of chro­mo­so­mal re­arrange­ment. New tech­nolo­gies, like Metageno­mi’s base ed­i­tors, elim­i­nate the need to cre­ate a dou­ble-strand break.

Huang not­ed that while Mod­er­na is look­ing for al­ter­na­tives to dou­ble-strand break to avoid risk where pos­si­ble, chro­mo­so­mal re­arrange­ment is not fre­quent­ly re­port­ed. Cha­puis point­ed to the field’s del­i­cate bal­anc­ing act in work­ing to re­duce risk while rec­og­niz­ing that the pa­tients re­ceiv­ing mod­i­fied cells are typ­i­cal­ly end-stage pa­tients in phase one tri­als.

Look­ing to­ward a fu­ture of pos­si­bil­i­ties

The en­er­gy around gene edit­ing is here to stay, pan­elists agreed. “One of the big rea­sons why there is so much ex­cite­ment about gene edit­ing is that this is the path to cu­ra­tive ther­a­pies…. That’s where the in­dus­try re­al­ly wants to go,” not­ed mod­er­a­tor John Car­roll of End­points News. “They want to come up with cu­ra­tive ther­a­pies … rather than just con­trol symp­toms or keep peo­ple on a steady plane.”

Not­ing the ex­is­tence of thou­sands of dif­fer­ent can­cers and the re­al­i­ty that few­er than 10 per­cent of rare dis­ease have ther­a­pies – with cures rar­er still — Dere ac­knowl­edged that “when you look at our abil­i­ty to cure pa­tients or to pro­vide long­stand­ing re­mis­sions, we have a ways to go still, a long ways to go.” But as­sess­ing the field af­ter decades in aca­d­e­m­ic and in­dus­try, he sees a world of hope. “The breadth of pos­si­bil­i­ties with gene edit­ing, with the ap­proach and the plat­forms that Metageno­mi pro­vides, are re­al­ly quite sig­nif­i­cant …. The pos­si­bil­i­ties here for more tar­get­ed, more spe­cif­ic and more ef­fi­cient gene edit­ing are tremen­dous,” he em­pha­sized. “With the pan­dem­ic, the emer­gence and crit­i­cal im­por­tance of the plat­form of mes­sen­ger RNA in terms of ther­a­peu­tics is in­cred­i­ble.”

Har­ness­ing the po­ten­tial of metage­nomics is what mo­ti­vates Thomas’ team to dri­ve for­ward. “When you start to wade through this in­cred­i­ble da­ta from these or­gan­isms that we’ve nev­er seen be­fore, we’ve nev­er stud­ied in a lab or cul­ti­vat­ed, it be­comes re­al­ly ex­cit­ing that there are pos­si­bil­i­ties there that we’re just now be­gin­ning to un­der­stand,” he said.