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.

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His­toric drug pric­ing re­forms pass; Pfiz­er ac­quires GBT; The long search for non-opi­oid pain drugs; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

The Endpoints Weekly has officially crossed the 60,000 mark on subscribers — thanks to all of your support. As the editorial team grows, we’ve been able to do a lot more, with many of those on display this week. Be sure to check out Lei Lei Wu’s deep dive on pain R&D. If you missed it, you may also rewatch her companion panel here.

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Gold for adults, sil­ver for in­fants: Pfiz­er's Pre­vnar 2.0 head­ed to FDA months af­ter Mer­ck­'s green light

Pfizer was first to the finish line for the next-gen pneumococcal vaccine in adults, but Merck beat its rival with a jab for children in June.

Now, two months after Merck’s 15-valent Vaxneuvance won the FDA stamp of approval for kids, Pfizer is out with some late-stage data on its 20-valent shot for infants.

Known as Prevnar 20 for adults, Pfizer’s 20vPnC will head to the FDA by the end of this year for an approval request in infants, the Big Pharma said Friday morning. Discussions with the FDA will occur first and more late-stage pediatric trials are expected to read out soon, informing the regulatory pathway in other countries and regions.

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Seagen interim CEO Roger Dansey and Daiichi Sankyo CEO Sunao Manabe

Paving the way for Mer­ck­'s buy­out, Seagen los­es ar­bi­tra­tion dis­pute with Dai­ichi over ADC tech

As Seagen awaits a final buyout offer from Merck that could be in the territory of $40 billion, Seagen revealed Friday afternoon that it lost an arbitration dispute with Daiichi Sankyo relating to the companies’ 2008 collaboration around the use of antibody-drug conjugate (ADC) technology.

But that loss likely won’t matter much when it comes to Merck’s deal.

After breaking off its pact with Daiichi in mid-2015, the two companies battled over “linker” tech — a chemical bridge between an ADC’s antibody component and the cytotoxic payload — that Seagen claims Daiichi would improve upon and implement in its current generation of ADCs.

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Benjamin Oakes, Scribe Therapeutics CEO

CEO of Doud­na spin­out: With­in five years, genome ed­i­tors will have a 're­al­ly big im­pact' on pa­tients' lives

“CRISPR-by-design” is the idea behind Scribe Therapeutics, a company spun out from Jennifer Doudna’s Nobel-winning lab that’s competing in a closely-tracked field of genome editor companies just starting to make their way to the clinic.

After nabbing $100 million last March for its Series B funding round, Scribe is taking a different tack from some of its competitors, crafting a new enzyme isolated from bacteria called CasX, which has now been tweaked extensively and may be targeted to a range of genome-related diseases, offering a plethora of therapeutic options.

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House pass­es his­toric drug pric­ing re­forms, lin­ing up decades-in-the-mak­ing win for Biden and De­moc­rats

The US House of Representatives today voted along party lines (all Dems voted for it), 220-207 to pass new, wide-ranging legislation that will allow Medicare drug price negotiations for the first time ever, and cap seniors’ drug expenses to $2,000 per year and seniors’ insulin costs at $35 per month.

Setting up a major victory for President Joe Biden, representatives returned from their summer recess to pass the Inflation Reduction Act, even as many noted the bill would only modestly reduce inflation.

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Senate Finance Committee Chair Ron Wyden (D-OR) (Francis Chung/E&E News/POLITICO via AP Images)

Sen­ate Fi­nance chair con­tin­ues his in­ves­ti­ga­tion in­to phar­ma tax­es with re­quests for Am­gen

Amgen is the latest pharma company to appear on the radar of Senate Finance Committee Chair Ron Wyden (D-OR), who is investigating the way pharma companies are using subsidiaries in low- or zero-tax countries to lower their tax bills.

Like its peers Merck, AbbVie and Bristol Myers Squibb, Wyden notes how Amgen uses its Puerto Rico operations to consistently pay tax rates that are substantially lower than the U.S. corporate tax rate of 21%, with an effective tax rate of 10.7% in 2020 and 12.1% in 2021.

FDA ap­proves sec­ond in­di­ca­tion for As­traZeneca and Dai­ichi's En­her­tu in less than a week

AstraZeneca and Daiichi Sankyo’s antibody-drug conjugate Enhertu scored its second approval in less than a week, this time for a subset of lung cancer patients.

Enhertu received accelerated approval on Thursday to treat adults with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, and who have already received a prior systemic therapy.

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J&J to re­move talc prod­ucts from shelves world­wide, re­plac­ing with corn­starch-based port­fo­lio

After controversially spinning out its talc liabilities and filing for bankruptcy in an attempt to settle 38,000 lawsuits, Johnson & Johnson is now changing up the formula for its baby powder products.

J&J is beginning the transition to an all cornstarch-based baby powder portfolio, the pharma giant announced on Thursday — just months after a federal judge ruled in favor of its “Texas two-step” bankruptcy to settle allegations that its talc products contained asbestos and caused cancer. An appeals court has since agreed to revisit that case.