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‘Mini liver’ will grow in person’s own lymph node in bold new trial

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A person has received an experimental treatment for the first time that, if successful, will lead them to grow an additional, ‘miniature liver’. The procedure, developed by the biotechnology firm LyGenesis, marks the beginning of a clinical trial designed for people whose livers are failing, but who have not received an organ transplant.

The approach is unusual: researchers injected healthy liver cells from a donor into a lymph node in the upper abdomen of the person with liver failure. The idea is that in several months, the cells will multiply and take over the lymph node to form a structure that can perform the blood-filtering duties of the person’s failing liver.

“It’s a very bold and incredibly innovative idea,” says Valerie Gouon-Evans, a liver-regeneration specialist at Boston University in Massachusetts, who is not involved with the company.

The person who received the treatment, on 25 March, is recovering well from the procedure and was discharged from the clinic, says Michael Hufford, chief executive of LyGenesis, which is based in Pittsburgh, Pennsylvania. But physicians will need to closely monitor them for infection because the person needs to take immunosuppressive drugs so that their body doesn’t reject the donor cells, says Stuart Forbes, a hepatologist at the University of Edinburgh, UK, who is not affiliated with LyGenesis.

Organ crisis

More than 50,000 people in the United States die each year with liver disease. In the end stage of the disease, scar tissue that has accumulated prevents the organ from filtering toxic substances in the blood, and can lead to infection or liver cancer.

A liver transplant can help, but there is a shortage of organs: about 1,000 people in the United States die every year waiting for a transplant. Thousands more aren’t eligible because they are too ill to undergo the procedure.

Gloved hands holding up a fluid bag of the donor liver cells in a lab.

A person received donor liver cells on 25 March that were injected into one of their lymph nodes.Credit: LyGenesis

LyGenesis has been trialling an approach that could help people in this situation — and make use of donated livers that would otherwise go to waste because a person on the transplant waiting list with a compatible health profile hasn’t materialized in time. The company’s strategy delivers the donor cells through a tube in the throat, injecting them into a lymph node near the liver. Lymph nodes, which also filter waste in the body and are an important part of the immune system, are ideal for growing mini livers, Hufford says, because they receive a large supply of blood and there are hundreds of them throughout the body, so if a few are used to generate mini livers, plenty of others can continue to function as lymph nodes.

The treatment has so far worked in mice1, dogs and pigs2. To test the therapy in pigs, researchers restricted blood flow to the animals’ livers, causing the organs to fail, and injected donor cells into lymph nodes. Miniature livers formed within two months and had a cellular architecture resembling a healthy liver. Researchers even found cells that transport bile, a digestive fluid produced by the liver, in the mini livers of the pigs. In this case, they saw no build-up of bile acid, suggesting that the mini organs were processing the fluid.

Hufford says there’s reason to think that the organs won’t grow indefinitely in the lymph nodes. The mini organs rely on chemical distress signals from the failing liver to grow; once the new organs have stabilized blood filtering, they will stop growing because that distress signal disappears, he says. But it’s not yet clear precisely how large the mini-livers will become in humans, he adds.

The company aims to enrol 12 people into the phase II trial by mid-2025 and publish results the following year, Hufford says. The trial, which was approved by US regulators in 2020, will not only measure participant safety, survival time and quality of life post-treatment, but will also help to establish the ideal number of mini livers to stabilize someone’s health. The clinicians running the trial will inject liver cells in up to five of a person’s lymph nodes to determine whether the extra organs can boost the procedure’s success rate.

A stop-gap measure

However, mini livers might not relieve all of the complications of end-stage liver disease, says Forbes, who has formed his own company to tackle liver disease using genetically modified immune cells that stimulate repair. One of the most serious of these is portal hypertension, in which the build-up of scar tissue compresses blood vessels in the liver and can cause internal bleeding.

Hufford acknowledges that the mini livers are not expected to address portal hypertension, but the hope is that they can provide a stopgap until a liver becomes available for transplant, or make people healthy enough to undergo a transplant. “That would be amazing, because these patients currently have no other treatment options,” Gouon-Evans says.

LyGenesis has ambitions beyond mini livers, too. The company is now testing similar approaches to grow kidney and pancreas cells in the lymph nodes of animals, Hufford says.

If the liver trial is successful, Gouon-Evans says, it would be worth investigating whether a person’s own stem cells could be used to generate the cells that seed the lymph nodes. This technique could create personalized cells that capture the diversity of cells in the liver and don’t require immunosuppressive drugs, she says.

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First pig liver transplanted into a person lasts for 10 days

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A shopkeeper holds a Bama miniature pig in a cafe offering customers relaxing access to the pet pigs in a shopping mall in Shanghai, China.

Organs from genetically modified pigs could help keep patients alive while they are awaiting a human donor.Credit: Feature China/Future Publishing via Getty

In a milestone for the transplantation of animal organs into people, a 50-year-old clinically dead man in China has become the first person to receive a liver from a pig. With consent from the man’s family, researchers stitched the organ, from a genetically engineered miniature pig, to the man’s blood vessels, where it remained for ten days. It has been surgically removed today, says Dou Kefeng, one of the surgeons who led the transplant at Xijing Hospital of the Air Force Medical University in Xi’an. “Our study has just been terminated, and the colour and texture of the pig liver [transplant] are generally normal.”

The procedure was intended to test whether genetically modified pig organs could one day be used to supply hospitals for transplants. In China alone, hundreds of thousands of people experience liver failure every year, but only around 6,000 received a liver transplant in 2022. In the past few years, surgeons in the United States have transplanted pig hearts into two living people, and transplanted hearts and kidneys to several people declared dead because they lack brain function.

The Xijing surgeons say the pig liver secreted more than 30 millilitres of bile every day, a sign that it was functioning.

Researchers who specialize in transplanting animal organs into people, known as xenotransplantation, are eager to see more details about the procedure’s safety and functional benefits, and to learn from the work.

“This is a really exciting study,” says Ping Li, a transplant researcher at Indiana University School of Medicine in Indianapolis.

Important insights

The surgery marks the first time a pig liver has been transplanted into a human. However, in January, a team led by transplant surgeon Abraham Shaked at the University of Pennsylvania in Philadelphia connected a clinically dead person to a genetically modified pig’s liver located outside their body. The organ circulated the person’s blood for three days.

It is “heart-warming” to see researchers pursuing xenotransplantation all over the world, says Muhammad Mohiuddin, the surgeon and researcher who led the pig-heart transplants in living people. “It’s an expensive process, but it has a huge amount of potential,” says Mohiuddin, who is at the University of Maryland School of Medicine in Baltimore and is president of the International Xenotransplantation Association.

Luhan Yang, chief executive of Qihan Biotech in Hangzhou, China, which is developing gene-edited pigs as a source for organs, says she expects more xenotransplants in clinically dead people or — for compassionate reasons — in terminally ill people in the United States, China and Europe in the coming years.

The Chinese study will offer important insights into whether pig-liver transplants can keep people alive, even just for a few days, says David Cooper, a xenotransplant immunologist at Massachusetts General Hospital in Boston.

Ten days

On 10 March, the Xijing Hospital team, including Dou, Tao Kaishan and Wang Lin transplanted a pig liver weighing 700 grams into the donor, who lacked cognitive function. The surgery took roughly nine hours to perform. The donor received a daily regimen of immunosuppressive drugs, and his original liver was left in place.

The liver came from a Bama miniature pig (Sus scrofa domestica) bred by the company Clonorgan Biotechnology in Chengdu, China. It contained six genetic modifications, says Wang. These deactivated three genes for proteins found on the surface of pig cells and introduced three genes for human proteins, to prevent the donor from rejecting the pig organ.

Dou says the pig was bred in a specialized pathogen-free facility and tested negative for about a dozen pathogens, including Streptococcus suis, the type-2 strain of Mycoplasma pneumoniae and porcine cytomegalovirus. So far, he has not seen signs of an immediate form of organ rejection and the liver is producing bile. “This is encouraging,” says Cooper.

The researchers have also taken daily blood samples and liver biopsies and will assess immune response, infection risk and liver function in detail. “We’re having a pathologist evaluate if there’s acute rejection,” says Dou.

The surgery was approved by the recipient’s family and several university committees, says Wang. “It has been strictly carried out according to relevant national and international regulations.”

Temporary fix?

The researchers plan to repeat the procedure in another clinically dead person later this year — and next time they will remove the person’s existing liver.

Mohiuddin points out that although clinically dead people are a useful model for assessing the viability of xenotransplantation in living people, that usefulness is limited, because once a person’s brain ceases activity, they undergo hormonal changes. And it isn’t yet clear how long someone with no cognitive function can be maintained on a ventilator and with a donated pig organ, he says. The longest documented case was two months, which involved a pig-kidney transplant.

Shaked also questions whether surgery is necessary for pig livers to be useful to humans. Unlike the heart, which essentially functions as a pump, the liver performs many complex tasks, which makes it particularly difficult to transplant. A pig liver can carry out the liver’s detoxifying and waste-disposal role, but Shaked does not anticipate that it will be able to produce the broad array of proteins required for the human liver’s other functions.

This means that whereas heart and kidney xenotransplants have been touted as possible long-term organ replacements, liver xenotransplants are seen mainly as a short-term fix for people with liver failure. They could enable a person’s existing liver to regenerate, for example after damage caused by alcohol or drug consumption, or could buy time while waiting for a human liver donor.

As a result, Shaked and his team chose to avoid operating: they hooked up an external pig liver to the recipient using blood-carrying tubes. But Dou says his team’s goal is organ replacement. He adds that working in a person allows the researchers to collect a lot more data, including information on immunology and physiological changes.

Yang says she hopes the team will publish detailed insights about the transplantation in peer-reviewed publications, to help determine which approach is more feasible.

In the meantime, Shaked hopes to exchange notes with the Chinese team. “I’d love to hear more about what they did. It’s fantastic.”

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First US drug approved for a liver disease surging around the world

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Coloured TEM of a section through liver tissue in a case of hepatic steatosis (fatty liver disease).

Liver tissue from a person with extra fat in the organ.Credit: IKELOS GmbH/Dr. Christopher B. Jackson/Science Photo Library

For the first time, the US Food and Drug Administration has approved a drug to treat an obesity-linked liver disease that is on the rise around the globe and is becoming a leading driver of liver failure and transplants.

The drug, called resmetirom, has been shown to reduce scar tissue in the liver and other hallmarks of a disease called metabolic dysfunction-associated steatohepatitis (MASH). MASH is often associated with the metabolic turmoil that can accompany obesity and diabetes, and in severe cases can lead to liver failure or cancer.

The disease affects an estimated 5% of the world’s adults. “It’s a huge population,” says Na Li, a hepatologist at Ohio State University Wexner Medical Center in Columbus. “And I think we have made a big step forward to improve their care.”

Worth the wait?

That step has been a long time coming: despite the clear need, pharmaceutical companies have struggled to develop a successful treatment for MASH. Last year, Intercept Pharmaceuticals in Morristown, New Jersey, abandoned a highly anticipated drug called obeticholic acid, amid concerns from the US Food and Drug Administration (FDA) that its modest effectiveness was not enough to outweigh safety risks.

“Many trials over the years have failed, even those that initially looked promising,” says Li. “That’s the tragedy we’ve had.”

MASH is caused by an accumulation of toxic, fatty molecules in the liver. Over time, this leads to inflammation and tissue damage. As the liver begins to accumulate scar tissue, a process called fibrosis, its ability to function declines. (MASH was called nonalcoholic steatohepatitis, or NASH, until professional societies adopted new nomenclature last year.)

Resmetirom boosts the liver’s ability to respond to thyroid hormone, which in turn stimulates the organ’s metabolism of fatty acids. In a year-long, multinational clinical trial in 966 people with MASH, researchers found that the drug reduced inflammation and fat build-up in 30% of participants who received the highest dose of resmetirom, compared with about 10% of those who took a placebo1. Fibrosis improved in about 26% of the highest-dose group, compared with 14% of the placebo group, making resmetirom the first candidate MASH drug to reduce fibrosis. It will be marketed as Rezdiffra and will be available to people with moderate to severe liver scarring.

Long-term benefits in doubt

The drug’s effectiveness, coupled with relatively mild side effects, was exciting and suggested that there could finally be a way to treat MASH, says Maya Balakrishnan, a gastroenterologist at Baylor College of Medicine in Houston, Texas. But the FDA granted resmetirom accelerated approval: for the drug to stay on the market, its developer, Madrigal Pharmaceuticals in Conshohocken, Pennsylvania, will eventually need to provide long-term evidence that it produces meaningful benefits.

“Only time will tell,” says Balakrishnan. “In the end, what matters is: does this drug improve survival?”

In the meantime, researchers are eagerly anticipating results from a study of semaglutide, a popular weight-loss drug, against MASH. Weight loss has been associated with a reduction in MASH severity, but an early clinical trial of semaglutide in participants with MASH yielded mixed results: some hallmarks of the disease improved, but liver fibrosis did not2. Still, researchers hope that semaglutide could help, and that the larger ongoing trial will provide clearer results, says Li.

In the meantime, resmetirom could be the best recourse for people with MASH. But physicians must be clear about the limited data on the drug when they discuss resmetirom with their patients, says Balakrishnan.

Access will be another issue, she says. Many of the people most in need of treatment are members of disadvantaged communities in which obesity and diabetes are prevalent. They often have limited access to health care, and it’s not yet known how much resmetirom will cost. “Who are the patients who are going to be able to access the medication?” says Balakrishnan. “It’s definitely a big concern.”

Potential blockbuster

Access in other countries will have to wait. Madrigal Pharmaceuticals’ clinical trials of resmetirom focused on the United States, says Claudia Oliveira, a pathologist at the University of São Paulo in Brazil. “We did not get the opportunity to see this drug in patients in Latin America,” she says. “But we all have expectations about the drug, because the results of the trial were very, very interesting.”

“Madrigal is a small company and chose to focus on a more limited geographic footprint for our trials,” a spokesperson for the company told Nature.

That decision likely helped speed the company’s first approval, says Norberto Chavez Tapia, a hepatologist at Médica Sur in Mexico City. Soon, he predicts, resmetirom will be investigated in clinical trials around the world.

After that, depending on the drug’s price and effects on transplants and survival, resmetirom could be welcomed in many health-care systems, says Tapia: “It’s a very attractive drug for us, worldwide.”

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