From mice to dogs, and some­day man: George Church's gene ther­a­py cock­tail for ag­ing-re­lat­ed dis­eases

George Chruch Re­ju­ve­nate

Emerg­ing gene-ther­a­py tech­nol­o­gy could help dogs live health­i­er, if not longer, lives as man’s best friend.

A start­up called Re­ju­ve­nate Bio — launched out of George Church’s lab at Har­vard Med­ical School (HMS) and the Wyss In­sti­tute for Bi­o­log­i­cal­ly In­spired En­gi­neer­ing at Har­vard Uni­ver­si­ty — on Thurs­day, with big plans to make work on gene ther­a­py tech­nol­o­gy en­gi­neered to pre­vent and treat a slew of age-re­lat­ed dis­eases in dogs and ex­tend their healthspan.

“Sci­ence hasn’t yet found a way to make com­plex an­i­mals like dogs live for­ev­er, so the next best thing we can do is find a way to main­tain health for as long as pos­si­ble dur­ing the ag­ing process,” said Church in a re­port by the Wyss In­sti­tute.

As we age, the propen­si­ty to be af­flict­ed with dis­ease(s) ris­es. But dis­eases are typ­i­cal­ly re­searched and treat­ed in­di­vid­u­al­ly, and the ex­ist­ing ar­ma­men­tar­i­um of treat­ments does not ac­com­mo­date the in­ter­con­nect­ed­ness of ill­ness­es that arise in lock­step with age. So, Har­vard re­searchers took a macro-lev­el ap­proach to the prob­lem of age-re­lat­ed dis­eases and de­vel­oped a gene ther­a­py fo­cused on a tri­fec­ta of longevi­ty as­so­ci­at­ed genes: FGF21, αK­lotho and sTGF𝝱R2 — which have pre­vi­ous­ly been shown to be as­so­ci­at­ed with in­creased health and lifes­pan ben­e­fits in mice that were ge­net­i­cal­ly en­gi­neered to over­ex­press them.

“We be­lieve that gene ther­a­py is a great tool for ac­tu­al­ly go­ing af­ter chron­ic age-re­lat­ed con­di­tions, par­tic­u­lar­ly if you have tar­get sets that have re­al­ly strong safe­ty pro­files,” Re­ju­ve­nate CEO Daniel Oliv­er said in an in­ter­view with End­points News.

“The genes we’re us­ing in­side of our gene ther­a­pies have been shown in trans­genic mouse mod­els to ex­tend their life. And so we have built-in safe­ty pro­files for the genes we’re us­ing — we have three-plus years of safe­ty da­ta in mice be­fore we even start.”

Noah David­sohn Re­ju­ve­nate

The re­searchers cre­at­ed sep­a­rate gene ther­a­py de­liv­ery ve­hi­cles for each gene us­ing a serotype of ade­no-as­so­ci­at­ed virus (AAV8) and then in­ject­ed the AAV con­structs in­to mouse mod­els of obe­si­ty, type II di­a­betes, heart fail­ure, and re­nal fail­ure to as­sess ef­fi­ca­cy.

The da­ta were strik­ing. FGF21 alone caused a com­plete re­ver­sal of weight gain and type II di­a­betes in obese, di­a­bet­ic mice fol­low­ing a sin­gle shot, and a com­bi­na­tion with sTGF𝝱R2 al­so di­min­ished kid­ney at­ro­phy by 75% in mice with re­nal fi­bro­sis. The gene sTGF𝝱R2 alone and in com­bi­na­tion with ei­ther of the oth­er two gene ther­a­pies im­proved heart func­tion in mice with heart fail­ure, sug­gest­ing that that co-ad­min­is­tra­tion of FGF21 and sTGF𝝱R2 could treat all four age-re­lat­ed con­di­tions.

To be sure, in this ini­tial study in mice the in­ject­ed genes did not stray in­to the an­i­mals’ genomes and did not mod­i­fy their nat­ur­al DNA — which is a con­cern giv­en the ex­ist­ing eu­genic prac­tices preva­lent in the pet in­dus­try.

Re­ju­ve­nate Bio on Thurs­day un­veiled plans to kick off a pi­lot study test­ing the ef­fi­ca­cy of this gene ther­a­py tech­nol­o­gy in ar­rest­ing mi­tral valve dis­ease, which af­fects most Cav­a­lier King Charles spaniels by age eight and caus­es heart fail­ure.

The plan is to en­roll 10 dogs with mi­tral valve dis­ease, in­ject them with the gene ther­a­py, and as­sess whether they progress to the next stage of the dis­ease over a giv­en pe­ri­od, Oliv­er said. This pi­lot study — which will take at least a year to read­out — will serve as a lit­mus test for an an­i­mal drug tri­al with the FDA, which tends to take about three years to com­plete. If all goes well, the com­pa­ny hopes to ex­pand the treat­ment to all ca­nine breeds, as more than 7 mil­lion dogs in the Unit­ed States suf­fer from mi­tral valve dis­ease.

“We want to get rid of the mor­bidi­ties as­so­ci­at­ed with ag­ing, so dogs can be as hap­py and healthy as pos­si­ble through­out their lives,” said Re­ju­ve­nate Bio’s chief tech­nol­o­gy of­fi­cer Noah David­sohn, who is a for­mer Re­search Sci­en­tist at the Wyss In­sti­tute and HMS. David­sohn’s dog, named Bear, serves as Re­ju­ve­nate’s “chief in­spi­ra­tion of­fi­cer.”

Bear David­sohn Re­ju­ve­nate

The first crop of FDA-ap­proved gene ther­a­pies for hu­mans — such as Spark Ther­a­peu­tics’ Lux­tur­na and No­var­tis’ Zol­gens­ma — treat rare dis­eases. If Re­ju­ve­nate’s ther­a­py is found to be safe and ef­fec­tive in dogs, it could open the door to sim­i­lar ther­a­pies for age-re­lat­ed ill­ness­es and in­deed ag­ing in hu­mans, a field that has at­tract­ed an ex­plo­sion of in­ter­est and fund­ing.

Al­though ear­ly, the study in mice showed that these so-called longevi­ty gene ther­a­pies can be com­bined in­to a sin­gle ther­a­peu­tic mix­ture — com­pared to the tra­di­tion­al par­a­digm that dic­tates dif­fer­ent dis­eases ne­ces­si­tate mul­ti­ple in­ter­ven­tions (and ar­guably ac­cu­mu­la­tive ex­po­sure to side-ef­fects), the re­searchers con­clud­ed.

In tan­dem with the ex­cite­ment that came in re­ac­tion to the FDA ap­proval of pi­o­neer­ing hu­man gene-ther­a­pies was the push­back on what some crit­ics call as­tro­nom­i­cal prices.  Zol­gens­ma, for in­stance, is the world’s most ex­pen­sive ther­a­py at $2.1 mil­lion a pop, al­though its mak­er No­var­tis in­sists its cu­ra­tive po­ten­tial and in­stall­ment-based pric­ing makes it worth it. The com­pa­ny has al­so ini­ti­at­ed a con­tro­ver­sial lot­tery scheme to give away 100 dos­es of Zol­gens­ma in coun­tries out­side the Unit­ed States where it is not yet ap­proved.

“I think go­ing for­ward as gene ther­a­py is ap­plied to dis­eases with much high­er preva­lence — you will see the price come down,” Oliv­er said.

Mean­while, the in­ter­est in treat­ing dis­eases in pets — if their hu­man own­ers may be so in­clined — is on the rise, giv­en that 67% of US house­holds, or about 85 mil­lion fam­i­lies, own a pet, ac­cord­ing to the 2019-2020 sur­vey con­duct­ed by the Amer­i­can Pet Prod­ucts As­so­ci­a­tion.

For in­stance, to treat dis­eases like can­cer in dogs — surgery, chemother­a­py, or ra­di­a­tion are ex­ist­ing al­ter­na­tives. But tar­get­ed ther­a­pies are the next fron­tier. A Sil­i­con Val­ley start­up — called the One Health Com­pa­ny — raised $5 mil­lion last month to help fig­ure out which hu­man treat­ments can be re­pur­posed for their ca­nine coun­ter­parts. The com­pa­ny, which likened its tech­nol­o­gy to Foun­da­tion Med­i­cine’s next-gen­er­a­tion se­quenc­ing pan­el in an in­ter­view with STAT, helps se­quence the dog’s tu­mor and gen­er­ates rec­om­men­da­tions for treat­ment.

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

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

'Al­tos was re­al­ly a once-in-a-life­time op­por­tu­ni­ty': Hal Bar­ron re­flects on his big move

By all accounts, Hal Barron had one of the best jobs in Big Pharma R&D. He made more than $11 million in 2020, once again reaping more than his boss, Emma Walmsley, who always championed him at every opportunity. And he oversaw a global R&D effort that struck a variety of big-dollar deals for oncology, neurodegeneration and more.

Sure, the critics never let up about what they saw as a rather uninspiring late-stage pipeline, where the rubber hits the road in the Big Pharma world’s hunt for the next big near-term blockbuster, but the in-house reviews were stellar. And Barron was firmly focused on bringing up the success rate in clinical trials, holding out for the big rewards of moving the dial from an average 10% success rate to 20%.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 129,300+ biopharma pros reading Endpoints daily — and it's free.

FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 129,300+ biopharma pros reading Endpoints daily — and it's free.

Kenneth Galbraith, incoming Zymeworks CEO

Zymeworks re­places half its C-suite, aims to lay off 25% of to­tal work­force as new CEO takes over

New Zymeworks CEO Kenneth Galbraith is aiming to hit the ground running when his tenure officially begins next month, but he’ll be doing so with a much different looking team.

In a lengthy press release outlining the biotech’s 2022 goals, Galbraith said Zymeworks will be laying off at least 25% of its staff over the course of the year. Half of its C-suite will also be replaced immediately as Galbraith looks to remake the company in his image after Ali Tehrani, Zymeworks’ founder and CEO since 2003, stepped down two weeks ago.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 129,300+ biopharma pros reading Endpoints daily — and it's free.

CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.