George Church (Mary Altaffer/AP Images)

George Church and an en­tre­pre­neur­ial post­doc join the hunt for AAV 2.0 with a new vec­tor-cloak­ing tech­nol­o­gy

About five years ago, George Church and his new post­doc, Ying Kai Chan, sat hunched over a lap­top in the ge­net­ics pi­o­neer’s Har­vard of­fice and stared in be­wil­der­ment at an old pa­per.

The pa­per doc­u­ment­ed ear­ly tri­als for Gly­bera, the first and at the time on­ly gene ther­a­py ap­proved any­where on the plan­et. Less than three dozen pa­tients ever re­ceived it, but in the years be­fore Lux­tur­na and Zol­gens­ma, it gave re­searchers an ex­am­ple they could point to for gene ther­a­py ac­tu­al­ly work­ing.

Chan and Church, though, were shocked to see that re­searchers run­ning clin­i­cal tri­als had giv­en pa­tients a bat­tery of high dose im­muno­sup­pres­sive drugs of­ten re­served for or­gan trans­plants, names like my­cophe­no­lic acid and cy­closporine. And when they biop­sied pa­tients’ mus­cles, they were filled with T cells, sug­gest­ing an im­mune re­sponse in ac­tion.

The re­sults were par­tic­u­lar­ly sur­pris­ing be­cause Gly­bera used the vi­ral vec­tor AAV, a de­liv­ery sys­tem that had led to a resur­gence in gene ther­a­py pre­cise­ly be­cause it was com­mon­ly be­lieved to evade the im­mune over­re­ac­tion that doomed the field in the 90s.

Ying Kai Chan

“There are so many peo­ple work­ing on gene ther­a­py now and even when you tell them, oh, ‘Did you know cy­closporin was used? Did you know all these things were used?’ Peo­ple are like, ‘Huh, what?” Chan told End­points News. “Gly­bera was the poster child, but it seems peo­ple didn’t ap­pre­ci­ate how much im­muno­sup­pres­sion was re­quired.”

Chan trained as a vi­ral im­mu­nol­o­gist and he came in­to the Church lab with an in­tu­ition that vi­ral vec­tors, those hol­lowed out and souped up gene taxis, were still virus­es and still treat­ed by the body as such. Grad­u­al­ly, the field has come around to his view. Mul­ti­ple mon­key stud­ies showed that high dos­es of AAV could be tox­ic for cer­tain neu­rons, re­sults that com­pa­nies have re­luc­tant­ly ac­cept­ed. And last year, three deaths in a high-dose tri­al height­ened AAV safe­ty con­cerns, even if those have yet to be linked con­clu­sive­ly to an im­muno­log­ic re­ac­tion.

Mean­while, Chan has been work­ing on new meth­ods of cloak­ing AAV to make it safer and re­duce the need for im­muno­sup­pres­sants. This week, he, Church, and a larg­er team at the Wyss In­sti­tute pub­lished the work in Sci­ence Trans­la­tion­al Med­i­cine, show­ing how weav­ing spe­cif­ic strands of hu­man DNA in­to the vec­tor can neu­tral­ize one of the body’s key de­fens­es against for­eign in­vaders.

“It was very much in­spired by na­ture,” Chan said.

One of the first ways gene ther­a­py pi­o­neer Jim Wil­son showed the body could re­act to AAV was through a set of sen­tinels called toll-like re­cep­tors. These sen­tinels pro­vide one of the im­mune sys­tem’s first lay­ers of de­fense, sound­ing an alarm if they de­tect any­thing that ap­pears for­eign. That means, though, that nor­mal cells need a way of telling the re­cep­tors they’re safe — an en­cryp­tion key that on­ly hu­man cells know.

That en­cryp­tion key is en­cod­ed in a few strands of DNA on the ends of telom­eres, those pa­per­clip-shaped strands at the end of chro­mo­somes that are some­times im­pli­cat­ed in ag­ing. Chan in­cor­po­rat­ed those strands in­to the DNA of an AAV2 vec­tor, the serotype used in Lux­tur­na. When the vec­tor is in­ject­ed, the strands should bind to the toll-like re­cep­tors through­out the body and tell the re­cep­tors not to sound any alarm.

When the team in­ject­ed it in­to the mus­cles, liv­er and eye of pig and mouse mod­els, it trig­gered a marked­ly re­duced im­mune re­ac­tion than a tra­di­tion­al vec­tor, Chan re­port­ed in STM.

The re­sults add to a suite of new tech­nolo­gies emerg­ing out of labs across the coun­try to com­bat AAV im­muno­genic­i­ty. Wil­son’s lab has of­fered a way of us­ing mi­croR­NAs — short strands that min­i­mize ex­pres­sion of a par­tic­u­lar­ly gene in a giv­en cell — to mit­i­gate the neur­al ef­fects. And Dyno Ther­a­peu­tics, a Church lab spin­out, us­es en­gi­neer­ing and ma­chine learn­ing to come up with whol­ly new vec­tors, with the hopes of find­ing some that can avoid the im­mune sys­tem.

Chan has now helped launch a new com­pa­ny, team­ing with ARCH and a cou­ple oth­er VCs to form Al­ly Ther­a­peu­tics, a still-in-stealth biotech that tries to min­i­mize the im­muno­genic­i­ty of vi­ral vec­tors.

Still, he ac­knowl­edges that he had hoped for more sweep­ing re­sults than he ul­ti­mate­ly had. Al­though his tech­nol­o­gy suc­cess­ful­ly tamped down the im­mune re­sponse in pigs and mice, the re­sults were less pro­found in mon­keys.

Chan’s team in­ject­ed the vec­tor in­to non-hu­man pri­mates’ eyes, a part of the body where much of the im­mune sys­tem can’t en­ter and, con­se­quent­ly, toll-like re­cep­tors are acute­ly im­por­tant. They saw im­proved safe­ty when they ad­min­is­tered be­neath the reti­na, but in­ject­ing it di­rect­ly in­to the vit­re­al jel­ly at the cen­ter of the eye still trig­gered sig­nif­i­cant in­flam­ma­tion. In­trav­it­re­al in­jec­tion is im­por­tant for tack­ling sev­er­al con­di­tions and for more broad­ly mak­ing oc­u­lar gene ther­a­pies safer and eas­i­er to de­liv­er, as on­ly eye sur­geons can ad­min­is­ter sub-reti­nal­ly.

The new pa­per, though, is just ver­sion 1.0 of the ap­proach, Chan said, and they’ve come up with sig­nif­i­cant im­prove­ments since.

More broad­ly, the field has a long way to go. An­i­mal mod­els, for ex­am­ple, are still poor pre­dic­tors of the im­mune re­sponse in hu­mans, mak­ing trans­la­tion dif­fi­cult and putting big holes in safe­ty tests. A vec­tor that ap­pears im­mune-silent in mon­keys could still trig­ger re­ac­tions in hu­mans and vice ver­sa. Al­though their role in an­i­mals is well-doc­u­ment­ed, it’s still not clear how great a role toll-like re­cep­tors play in the hu­man re­sponse to AAV.

Still, Chan says they ac­com­plished what they set out to do: They im­proved the vec­tor and, in the process, helped the field wake up to an is­sue that for years went over­looked.

“There are still chal­lenges,” Chan said. “What we re­al­ly want­ed to ac­com­plish was to raise aware­ness, as well as come up with a promis­ing so­lu­tion. I would say we made progress on both fronts.”

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.

Kristen Hege, Bristol Myers Squibb SVP, early clinical development, oncology/hematology and cell therapy (Illustration: Assistant Editor Kathy Wong for Endpoints News)

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Kristen Hege leads Bristol Myers Squibb’s early oncology discovery program carrying on from the same work at Celgene, which was acquired by BMS in 2019. She’s known for her early work in CAR-T, having pioneered the first CAR-T cell trial for solid tumors more than 25 years ago.

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Rick Modi, Affinia Therapeutics CEO

Ver­tex-part­nered gene ther­a­py biotech Affinia scraps IPO plans

Affinia Therapeutics has ditched its plans to go public in a relatively closed-door market that has not favored Nasdaq debuts for the drug development industry most of this year. A pandemic surge in 2020 and 2021 opened the doors for many preclinical startups, which caught Affinia’s attention and gave the gene therapy biotech confidence in the beginning days of 2022 to send in its S-1.

But on Friday, Affinia threw in the S-1 towel and concluded now is not the time to step onto Wall Street. The biotech has put out few public announcements since the spring of this year. Endpoints News picked the startup as one of its 11 biotechs to watch last year.

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Eisai and METAvivor plan to debut the latest 'This is MBC' campaign at the San Antonio Breast Cancer Symposium (SABCS).

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The new “Imagine” campaign features 12 patients photographed around waterfalls to symbolize that same kind of sudden drop into a pool that MBC causes in a person’s life, said Beth Fairchild, co-founder of #CancerCulture who was the president of METAvivor six years ago when the campaign began. Fairchild, who is living with MBC, has helped create all of the annual “This is MBC” campaigns.

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Pfiz­er and BioN­Tech look to toss Mod­er­na patent suit, call­ing claims 'unen­force­able'

Pfizer and BioNTech took a swing at Moderna’s Covid-19 patent claims in Massachusetts federal court on Monday, calling them “invalid,” “overbroad” and “unenforceable.”

The defendants also filed counterclaims against the Cambridge, MA-based biotech, seeking a dismissal of the case, recovery of court fees and an official judgment invalidating Moderna’s claims.

Moderna sued Pfizer and BioNTech back in August, alleging that the partners’ Covid-19 vaccine Comirnaty copied parts of Moderna’s vaccine technology patented before the pandemic, when it was developing an mRNA vaccine for MERS, another respiratory illness.

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Gossamer Bio CEO Faheem Hasnain at Endpoints' #BIO22 panel (J.T. MacMillan Photography for Endpoints News)

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According to the letter, the FDA found that Glenmark’s investigation of rejected batches of drugs “failed to extend to other batches, dosage strengths, and drug products.” The warning letter also noted that the site had failed to establish “adequate written procedures” for production and process control to ensure drugs have the correct strength, quality and purity.

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Klick literally lit up the Tony Stacey Centre for Veterans Care, a long-term care home in Toronto where 75% of residents receive no visitors during the holiday season. The agency brought staff and family along with lighting crews and musicians for a “Light the Way” event, creating a video of the experience debuting on Tuesday.

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Jay Lichter, Arialys Therapeutics CEO (Avalon Ventures)

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Arialys Therapeutics filed incorporation documents in the Golden State last December and applied its name for trademark protection with the US Patent and Trademark Office the week prior to that. Paperwork with the SEC also outlines plans to offer up equity in exchange for $55 million.

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