In step for­ward for re­ju­ve­na­tion field, re­searchers turn back the clock on mice hearts

When Thomas Braun was start­ing out as a young pro­fes­sor at Ger­many’s Uni­ver­si­ty of Würzburg in 1997, he de­cid­ed to try his hand at a new field: heart re­gen­er­a­tion, a sci-fi-es­que premise that could of­fer a way to treat pa­tients re­cov­er­ing from a heart at­tack. He thought it would take a few years be­fore they got re­sults.

“We were,” he ac­knowl­edges now, “rather naïve.”

Thomas Braun

But on Thurs­day, af­ter two and a half decades of fit­ful starts and aban­doned leads, Braun and a team of re­searchers at the Max Planck In­sti­tute showed that they could re­pro­gram heart cells in mice and get the an­i­mals to re­gen­er­ate car­diac tis­sue af­ter a heart at­tack. The break­through, pub­lished in Sci­enceadds new ev­i­dence that it will even­tu­al­ly be pos­si­ble to help pa­tients re­cov­er mus­cle lost in heart at­tacks and gives an­oth­er boon to an­ti-ag­ing re­searchers who want to one day ap­ply these re­ju­ve­na­tion tech­niques across much of the body.

It was not pre­vi­ous­ly clear whether re­ju­ve­na­tion tech­niques Braun de­ployed would work in car­diac cells, which are among the least ma­nip­u­lat­able in the body.

“It shows that it can be done in the heart,” said Payel Sen, a re­searcher at the Na­tion­al In­sti­tute on Ag­ing who wasn’t in­volved in the work. “And we know that car­dio­vas­cu­lar is­sues are one of the lead­ing caus­es of mor­tal­i­ty in ag­ing, so if we are able to re­pro­gram the heart, that would be im­pact­ful.”

Adults to­day have cho­les­terol-low­er­ing treat­ments that can help stave off heart at­tacks. And pa­tients who suf­fer such at­tacks can take be­ta-block­ers and one of a cou­ple new drugs to slow their de­cline.

Payel Sen

But their de­cline is ef­fec­tive­ly in­evitable; heart cells are some of the most in­flex­i­ble in the body. Un­like, say, the liv­er or mus­cle, they don’t re­gen­er­ate when in­jured. And that paints a grim prog­no­sis for peo­ple with heart fail­ure. Even in the piv­otal study for Mer­ck’s veri­ciguat, one of the new car­dio­vas­cu­lar drugs on the mar­ket, 16% of pa­tients who re­ceived the med­i­cine died in less than a year.

Over the years, re­searchers have tried var­i­ous ap­proach­es to in­duce heart cells, known as car­diomy­ocytes, to di­vide, rarely with luck. En­gi­neered stem cells be­came a pop­u­lar ap­proach for a while, af­ter a pur­port­ed break­through, but those re­sults large­ly van­ished in a cloud of scan­dal.

“Car­diomy­ocytes are re­al­ly, ex­treme­ly re­luc­tant to go in­to cell di­vi­sion,” said Braun, who now di­rects the Max Planck In­sti­tute for Heart and Lung Re­search.

About four years ago, Braun and a post­doc be­gan try­ing a new strat­e­gy, called Ya­mana­ka fac­tors. Dis­cov­ered in 2006, this cock­tail of pro­teins can turn a spe­cial­ized cell like a neu­ron back in­to a stem cell. Over the past decade, a hand­ful of re­searchers have tried to give these fac­tors to mice in a way that re­vers­es the signs and symp­toms of ag­ing.

James Mar­tin

In 2016, Juan Car­los Izpisua Bel­monte showed he could “re­ju­ve­nate” ag­ing mice with the fac­tors. Last year, Har­vard’s David Sin­clair used the ap­proach to re­store vi­sion in old blind mice. Jeff Be­zos and oth­er big Sil­i­con Val­ley names have re­cent­ly raised hun­dreds of mil­lions of dol­lars for a re­pro­gram­ming start­up called Al­tos Labs.

Braun sim­i­lar­ly thought the ap­proach could be his an­swer. And he had oth­er ev­i­dence to back it up; if you in­jured the heart of a fe­tal mouse, the fe­tus has lit­tle dif­fi­cul­ty re­gen­er­at­ing the or­gan. So Braun didn’t want to re­verse cells all the way to stem cell, just to their ear­li­er, still-di­vid­ing fe­tal state.

“What if we turned back the clock?” he asked. “From an adult heart mus­cle cell to a younger one?”

That turned out to be painstak­ing work. It wasn’t clear how many of the Ya­mana­ka fac­tors the heart cells would need to re­vert back to fe­tal state. Too lit­tle and they wouldn’t re­gen­er­ate. Too much and you could make the cells for­get their iden­ti­ty and for­mer tu­mors.

Can­cer, a dis­ease where cells pro­lif­er­ate be­yond con­trol, has been the con­stant thorn in re­pro­gram­ming’s side. Many of Bel­monte’s mice showed signs of age re­ver­sal but many of them died of can­cer with­in days of treat­ment.

For the ex­per­i­ment, Braun bio-en­gi­neered mice so that they can ex­press Ya­mana­ka fac­tors, but on­ly when they’re fed a cer­tain an­tibi­ot­ic. Af­ter four years of tin­ker­ing, he found one fac­tor recipe that he be­lieved would work.

To test the the­o­ry, he treat­ed mice with the an­tibi­ot­ic to get them to ex­press the fac­tors be­fore in­duc­ing in them a mas­sive heart at­tack. He al­so tried in­duc­ing a mas­sive heart at­tack one day af­ter. In both cas­es, heart cells grew back and heart func­tion im­proved.

“It’s ex­cit­ing,” said James Mar­tin, a Bay­lor Col­lege of Med­i­cine re­searcher who’s de­vel­op­ing a sep­a­rate gene ther­a­py to re­gen­er­ate heart tis­sue. “It opens the door to fur­ther de­vel­op­ment of treat­ment.”

Mar­tin, though, doesn’t ex­pect that Braun’s ap­proach it­self will be­come a treat­ment. In ad­di­tion to the dif­fi­cul­ty of de­liv­er­ing these fac­tors in­to a pa­tient — vi­ral vec­tors are a pos­si­ble but im­per­fect so­lu­tion — the re­gen­er­a­tion they saw was lim­it­ed.

A third group of mice who were treat­ed just six days af­ter the heart at­tack didn’t see any ben­e­fit, mean­ing the win­dow for treat­ing pa­tients would be tiny.

“I don’t think this would work for most heart fail­ure pa­tients,” Mar­tin said.

Still, the re­sults pro­vide fur­ther ev­i­dence that it will one day be fea­si­ble to re­gen­er­ate heart tis­sue in pa­tients, Mar­tin said. And if heart cells can be re­pro­grammed, then like­ly oth­er non-di­vid­ing tis­sues can be too, a boon to the broad re­ju­ve­na­tion field.

Re­searchers, for ex­am­ple, have spent decades try­ing to fig­ure out how to re­gen­er­ate spinal cords af­ter in­jury.

Braun’s study, though, al­so points to the dif­fi­cul­ty that the field will en­counter. Heart can­cer is one of the rarest ma­lig­nan­cies, af­fect­ing less than 2 out of 100,000 peo­ple. But mice in the study who ex­pressed Ya­mana­ka fac­tors for too long man­aged to de­vel­op tu­mors in the heart.

If heart cells can be re­pro­grammed, any cell prob­a­bly can. And, Sen said, if re­pro­grammed heart cells can de­vel­op can­cer, then prob­a­bly any cell — if re­pro­grammed in­cor­rect­ly — can too.

“One can’t hide,” said Braun. “It’s a dan­ger­ous game.”

M&A: a crit­i­cal dri­ver for sus­tain­able top-line growth in health­care

2021 saw a record $600B in healthcare M&A activity. In 2022, there is an anticipated slowdown in activity, however, M&A prospects remain strong in the medium to long-term. What are future growth drivers for the healthcare sector? Where might we see innovations that drive M&A? RBC’s Andrew Callaway, Global Head, Healthcare Investment Banking discusses with Vito Sperduto, Global Co-Head, M&A.

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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.

A return to in-person conferences also marks a return to on-the-ground reporting. My colleagues Beth Synder Bulik and Nicole DeFeudis were on-site at Cannes Lions, bringing live coverage of pharma’s presence at the ad festival — accompanied by photos from Clara Bui, our virtual producer, that bring you right to the scene. You can find a recap (and links to all the stories) below.

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Following the decision, the New England Journal of Medicine also published an editorial strongly condemning the reversal, saying it “serves American families poorly, putting their health, safety, finances, and futures at risk.”

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GSK says its drug for chron­ic hep B could ‘lead to a func­tion­al cure’ — but will it be alone or in com­bi­na­tion?

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At a presentation at the EASL International Liver Congress, GSK shared that in around 450 patients who received its hep B drug bepirovirsen for 24 weeks, just under 30% had hepatitis B surface antigen and viral DNA levels that were too low to detect.

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PwC pharmaceutical and life sciences consulting solutions leader Glenn Hunzinger expects to see Big Pharma companies picking up earlier stage companies to try and fill pipeline gaps ahead of a slew of big patent cliffs. Though a bear market continues to maul the biotech sector, Hunzinger said recent deals indicate that pharma companies are still paying above current trading prices.

Joe Wiley, Amryt Pharma CEO

Am­ryt Phar­ma sub­mits a for­mal dis­pute res­o­lu­tion to the FDA over re­ject­ed skin dis­ease drug

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After the Irish drugmaker’s candidate, dubbed Oleogel-S10 and marketed as Filsuvez, was handed a CRL earlier this year, the company announced in a press release that it plans to submit a formal dispute resolution request for the company’s NDA for Oleogel-S10.

Sen. Thom Tillis (R-NC) (J. Scott Applewhite/AP Images)

Phar­ma-friend­ly sen­a­tor calls on FDA for a third time to show patent pro­tec­tions should­n't be blamed for high drug prices

North Carolina Republican Sen. Thom Tillis made a name for himself in the 2020 election cycle as the darling of the pharma industry, accepting hundreds of thousands in campaign contributions, even from the likes of Pfizer CEO Albert Bourla.

Those contributions have led Tillis to attempt to re-write patent laws in pharma’s favor, a move which failed to gain steam in 2019, and request for a third time since January that the FDA should help stop “the false narrative that patent protections are to blame for high drug prices.”

EMA signs off on 3 drugs re­cent­ly re­ject­ed by FDA, in­clud­ing Bio­Mar­in's new he­mo­phil­ia gene ther­a­py

The EMA’s human medicines committee on Friday recommended three new drugs for approval or conditional approval, even as their US counterparts have rejected these three for various reasons.

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