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.”

Health­care Dis­par­i­ties and Sick­le Cell Dis­ease

In the complicated U.S. healthcare system, navigating a serious illness such as cancer or heart disease can be remarkably challenging for patients and caregivers. When that illness is classified as a rare disease, those challenges can become even more acute. And when that rare disease occurs in a population that experiences health disparities, such as people with sickle cell disease (SCD) who are primarily Black and Latino, challenges can become almost insurmountable.

Jacob Van Naarden (Eli Lilly)

Ex­clu­sives: Eli Lil­ly out to crash the megablock­buster PD-(L)1 par­ty with 'dis­rup­tive' pric­ing; re­veals can­cer biotech buy­out

It’s taken 7 years, but Eli Lilly is promising to finally start hammering the small and affluent PD-(L)1 club with a “disruptive” pricing strategy for their checkpoint therapy allied with China’s Innovent.

Lilly in-licensed global rights to sintilimab a year ago, building on the China alliance they have with Innovent. That cost the pharma giant $200 million in cash upfront, which they plan to capitalize on now with a long-awaited plan to bust up the high-price market in lung cancer and other cancers that have created a market worth tens of billions of dollars.

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So what hap­pened with No­var­tis' gene ther­a­py group? Here's your an­swer

Over the last couple of days it’s become clear that the gene therapy division at Novartis has quietly undergone a major reorganization. We learned on Monday that Dave Lennon, who had pursued a high-profile role as president of the unit with 1,500 people, had left the pharma giant to take over as CEO of a startup.

Like a lot of the majors, Novartis is an open highway for head hunters, or anyone looking to staff a startup. So that was news but not completely unexpected.

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Who are the women su­per­charg­ing bio­phar­ma R&D? Nom­i­nate them for this year's spe­cial re­port

The biotech industry has faced repeated calls to diversify its workforce — and in the last year, those calls got a lot louder. Though women account for just under half of all biotech employees around the world, they occupy very few places in C-suites, and even fewer make it to the helm.

Some companies are listening, according to a recent BIO survey which showed that this year’s companies were 2.5 times more likely to have a diversity and inclusion program compared to last year’s sample. But we still have a long way to go. Women represent just 31% of biotech executives, BIO reported. And those numbers are even more stark for women of color.

David Meek, new Mirati CEO (Marlene Awaad/Bloomberg via Getty Images)

Fresh off Fer­Gene's melt­down, David Meek takes over at Mi­rati with lead KRAS drug rac­ing to an ap­proval

In the insular world of biotech, a spectacular failure can sometimes stay on any executive’s record for a long time. But for David Meek, the man at the helm of FerGene’s recent implosion, two questionable exits made way for what could be an excellent rebound.

Meek, most recently FerGene’s CEO and a past head at Ipsen, has become CEO at Mirati Therapeutics, taking the reins from founding CEO Charles Baum, who will step over into the role of president and head of R&D, according to a release.

Jay Bradner (Jeff Rumans for Endpoints News)

Div­ing deep­er in­to in­her­it­ed reti­nal dis­or­ders, No­var­tis gob­bles up an­oth­er bite-sized op­to­ge­net­ics biotech

Right about a year ago, a Novartis team led by Jay Bradner and Cynthia Grosskreutz at NIBR swooped in to scoop up a Cambridge, MA-based opthalmology gene therapy company called Vedere. Their focus was on a specific market niche: inherited retinal dystrophies that include a wide range of genetic retinal disorders marked by the loss of photoreceptor cells and progressive vision loss.

But that was just the first deal that whet their appetite.

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Dave Lennon, former president of Novartis Gene Therapies

Zol­gens­ma patent spat brews be­tween No­var­tis and Re­genxbio as top No­var­tis gene ther­a­py ex­ec de­parts

Regenxbio, a small licensor of gene therapy viral vectors spun out from the University of Pennsylvania, is now finding itself in the middle of some major league patent fights.

In addition to a patent suit with Sarepta Therapeutics from last September, Novartis, is now trying to push its smaller partner out of the way. The Swiss biopharma licensed Regenxbio’s AAV9 vector for its $2.1 million spinal muscular atrophy therapy Zolgensma.

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The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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When ef­fi­ca­cy is bor­der­line: FDA needs to get more con­sis­tent on close-call drug ap­provals, agency-fund­ed re­search finds

In the exceedingly rare instances in which clinical efficacy is the only barrier to a new drug’s approval, new FDA-funded research from FDA and Stanford found that the agency does not have a consistent standard for defining “substantial evidence” when flexible criteria are used for an approval.

The research comes as the FDA is at a crossroads with its expedited-review pathways. The accelerated approval pathway is under fire as the agency recently signed off on a controversial new Alzheimer’s drug, with little precedent to explain its decision. Meanwhile, top officials like Rick Pazdur have called for a major push to simplify and clarify all of the various expedited pathways, which have grown to be must-haves for sponsors of nearly every newly approved drug.

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