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.”

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.

Christian Itin, Autolus CEO (UKBIO19)

Au­to­lus tips its hand, bags $220M as CAR-T show­down with Gilead looms

The first batch of pivotal data on Autolus Therapeutics’ CAR-T is in, and execs are ready to plot a path to market.

With an overall remission rate of 70% at the interim analysis featuring 50 patients, the results set the stage for a BLA filing by the end of 2023, said CEO Christian Itin.

Perhaps more importantly — given that Autolus’ drug, obe-cel, is going after an indication that Gilead’s Tecartus is already approved for — the biotech highlighted “encouraging safety data” in the trial, with a low percentage of patients experiencing severe immune responses.

Dipal Doshi, Entrada Therapeutics CEO

Ver­tex just found the next big ‘trans­for­ma­tive’ thing for the pipeline — at a biotech just down the street

Back in the summer of 2019, when I was covering Vertex’s executive chairman Jeff Leiden’s plans for the pipeline, I picked up on a distinct focus on myotonic dystrophy Type I, or DM1 — one of what Leiden called “two diseases (with DMD) we’re interested in and we continue to look for those assets.”

Today, Leiden’s successor at the helm of Vertex, CEO Reshma Kewalramani, is plunking down $250 million in cash to go the extra mile on DM1. The lion’s share of that is for the upfront, with a small reserve for equity in a deal that lines Vertex up with a neighbor in Seaport that has been rather quietly going at both of Vertex’s early disease targets with preclinical assets.

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WIB22: Am­ber Salz­man had few op­tions when her son was di­ag­nosed with a rare ge­net­ic dis­ease. So she cre­at­ed a bet­ter one

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

Amber Salzman’s life changed on a cold, damp day in Paris over tiny plastic cups of lukewarm tea.

She was meeting with Patrick Aubourg, a French neurologist studying adrenoleukodystrophy, or ALD, a rare genetic condition that causes rapid neurological decline in young boys. It’s a sinister disease that often leads to disability or death within just a few years. Salzman’s nephew was diagnosed at just 6 or 7 years old, and died at the age of 12.

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Ahead of ad­comm, FDA rais­es un­cer­tain­ties on ben­e­fit-risk pro­file of Cy­to­ki­net­ic­s' po­ten­tial heart drug

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will meet next Tuesday to discuss whether Cytokinetics’ potential heart drug can safely reduce the risk of cardiovascular death and heart failure in patients with symptomatic chronic heart failure with reduced ejection fraction.

The drug, known as omecamtiv mecarbil and in development for more than 15 years, has seen mixed results, with a first Phase III readout from November 2020 hitting the primary endpoint of reducing the odds of hospitalization or other urgent care for heart failure by 8%. But it also missed a key secondary endpoint analysts had pegged as key to breaking into the market.

Ab­b­Vie slapped with age dis­crim­i­na­tion law­suit, fol­low­ing oth­er phar­mas

Add AbbVie to the list of pharma companies currently facing age discrimination allegations.

Pennsylvania resident Thomas Hesch filed suit against AbbVie on Wednesday, accusing the company of passing him over for promotions in favor of younger candidates.

Despite 30 years of pharma experience, “Hesch has consistently seen younger, less qualified employees promoted over him,” the complaint states.

Rami Elghandour, Arcellx CEO

Up­dat­ed: Gilead, Ar­cel­lx team up on an­ti-BC­MA CAR-T as biotech touts a 100% re­sponse rate at #ASH22

Gilead and Kite are plunking down big cash to get into the anti-BCMA CAR-T game.

The pair will shell out $225 million in cash upfront and $100 million in equity to Arcellx, Kite announced Friday morning, to develop the biotech’s lead CAR-T program together. Kite will handle commercialization and co-development with Arcellx, and profits in the US will be split 50-50.

Concurrent with the deal, Arcellx revealed its latest cut of data for the program known as CART-ddBCMA, ahead of a full presentation at this weekend’s ASH conference — a 100% response rate among patients getting the therapy. Investors jumped at the dual announcements, sending Arcellx shares $ACLX up more than 25% in Friday’s morning session.

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WIB22: Lead­ing NK cell re­searcher re­flects on roots in Iran, the UK and Texas

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

In a small but widely-cited 11-person study published in NEJM in 2020, seven patients saw signs of their cancer completely go away after getting a new therapy made from natural killer cells. The study was one of the earliest to provide clinical proof that the experimental treatment method had promise.

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WIB22: Chas­ing af­ter ever-evolv­ing sci­ence takes a drug hunter across the pond

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

Like many scientists, Fiona Marshall would tell you that she loved the natural world growing up — going to look at crabs running around the beach near her childhood home, pondering about the tides. But one thing about biology, in particular, stood out: It was constantly changing, and changing very quickly.

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