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.”

Biotech and Big Phar­ma: A blue­print for a suc­cess­ful part­ner­ship

Strategic partnerships have long been an important contributor to how drugs are discovered and developed. For decades, big pharma companies have been forming alliances with biotech innovators to increase R&D productivity, expand geographical reach and better manage late-stage commercialization costs.

Noël Brown, Managing Director and Head of Biotechnology Investment Banking, and Greg Wiederrecht, Ph.D., Managing Director in the Global Healthcare Investment Banking Group at RBC Capital Markets, are no strangers to the importance of these tie-ups. Noël has over 20 years of investment banking experience in the industry. Before moving to the banking world in 2015, Greg was the Vice President and Head of External Scientific Affairs (ESA) at Merck, where he was responsible for the scientific assessment of strategic partnership opportunities worldwide.

Credit: Shutterstock

How Chi­na turned the ta­bles on bio­phar­ma's glob­al deal­mak­ing

Fenlai Tan still gets chills thinking about the darkest day of his life.

Three out of eight lung cancer patients who received a tyrosine kinase inhibitor developed by his company, Betta Pharma, died in the span of a month. Tan, the chief medical officer, was summoned to Peking Union Medical College Hospital, where the head of the clinical trial department told him that the trial investigators would be conducting an autopsy to see if the patients had died of the disease — they were all very sick by the time they enrolled — or of interstitial lung disease, a deadly side effect tied to the TKI class that’s been reported in Japan.

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Novartis’ hopes of turning one of the most surprising trial data points of the last decade into a lung cancer drug has taken another setback.

The Swiss pharma announced Monday that its IL-1 inhibitor canakinumab did not significantly extend the lives or slow the disease progression of patients with previously untreated locally advanced or metastatic non-small cell lung cancer when compared to standard of-care alone.

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Peter Nell, Mammoth Biosciences CBO

UP­DAT­ED: Jen­nifer Doud­na spin­out inks a Mam­moth CRISPR deal with Ver­tex worth near­ly $700M

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Mammoth unveiled a nearly $700 million deal with Vertex on Tuesday morning, good for the development of in vivo gene therapies for two mystery diseases. The stars of the show are Mammoth’s ultra-small CRISPR systems, including two Cas enzymes licensed from Doudna’s lab over the past couple years, Cas14 and Casɸ.

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An­gion's or­gan dam­age drug strikes out again, this time in high-risk kid­ney trans­plant pa­tients

After flopping a test in Covid-19 earlier this year, Angion’s lead organ damage drug has now hit the skids again in kidney transplant patients.

Angion and partner Vifor Pharma’s ANG-3777 failed to beat out placebo in terms of improving eGFR, a measure of kidney function, in patients who had received a deceased donor kidney transplant and were at high risk of developing what is known as delayed graft function, according to Phase III results released Tuesday.

(Photo courtesy Pfizer)

FDA's vac­cine ad­comm votes al­most unan­i­mous­ly in fa­vor of Pfiz­er's Covid-19 vac­cine for younger chil­dren

The FDA’s Vaccines and Related Biological Products Advisory Committee on Tuesday voted 17-0, with one panelist abstaining, that the benefits of the Pfizer-BioNTech Covid-19 vaccine outweigh the risks for children between the ages of five and 12.

The vote will likely trigger a process that could allow the shots to begin rolling out as early as next week.

The vaccine, which is one-third of the adult Pfizer dose, proved to be about 90% effective in a placebo-controlled trial in which about 1,500 kids in this age range received the vaccine, and only about 12% of those receiving the vaccine had any adverse event. All serious adverse events in the trial were unrelated to the vaccine.

Stéphane Bancel, Moderna CEO (Steven Ferdman/Getty Images)

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In a sign of its growing commitment to the continent, Moderna will supply up to 110 million doses of its Covid-19 vaccine to the African Union, the company announced Tuesday. And CEO Stéphane Bancel said it’s just the first step.

“We believe our vaccine can play an important role in addressing the needs of low-income countries given its combination of high Phase 3 efficacy against COVID-19, strong durability in the real-world evidence, and superior storage and handling conditions. We recognize that access to COVID-19 vaccines continues to be a challenge in many parts of the world and we remain committed to helping to protect as many people as possible around the globe,” Bancel said in a statement.

An image of Alzheimer's brain tissue. The red show gingipains, a protein from P. gingivalis, intermixing with neurons (yellow) and glial cells (green)

An Alzheimer's dark­horse fails its first big tri­al, but of­fers hope for a long-over­looked hy­poth­e­sis

Three years ago, Cortexyme emerged out of obscurity with some big-name backers and an unorthodox approach to treating Alzheimer’s.

They moved their drug into a pivotal study the next year, offering one of the first major tests for a hypothesis that has fluttered on the outskirts of Alzheimer’s research for decades: that, in many cases, the disease is driven by infectious agents — the havoc they wreak in the brain and the inflammation the body uses to try to fend them off. And that quashing the infection could slow patients’ cognitive decline.

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Ugur Sahin, AP Images

As pres­sure to share tech­nol­o­gy mounts, BioN­Tech se­lects Rwan­da for lat­est vac­cine site

BioNTech’s first mRNA-based vaccine site in Africa will call Rwanda home, and construction is set to start in mid-2022, the company announced Tuesday at a public health forum.

The German company signed a memorandum of understanding, after a meeting between Rwanda’s Minister of Health, Daniel Ngamije, Senegal’s Minister of Foreign Affairs Aïssata Tall Sall, and senior BioNTech officials. Construction plans have been finalized, and assets have been ordered. The agreement will help bring end-to-end manufacturing to Africa, and as many as several hundred million doses of vaccines per year, though initial production will be more modest.