这家公司即将第一次在一个人身上长出新的器官

StephenW

这家公司即将第一次在一个人身上长出新的器官

一名患有严重肝病的志愿者将很快接受一项可能导致他们长出第二个肝脏的手术。
经过

    杰西卡·哈姆泽卢档案页

2022 年 8 月 25 日


在接下来的几周内，马萨诸塞州波士顿的一名志愿者将率先尝试一种新的治疗方法，这种治疗方法最终可能会在他们的体内产生第二个肝脏。而这仅仅是开始——在接下来的几个月里，其他志愿者将测试可能使他们体内最多留有六个肝脏的剂量。

治疗背后的公司 LyGenesis 希望拯救那些不符合移植条件的患有破坏性肝病的人。他们的方法是将供体的肝细胞注射到患病受体的淋巴结中，这可以产生全新的微型器官。这些微型肝脏应该有助于补偿现有的患病肝脏。这种方法似乎适用于老鼠、猪和狗。现在我们将看看它是否适用于人。

如果它确实有效，那么治疗可能是革命性的。供体器官供不应求，许多捐赠的器官无法使用——例如，有时组织损伤太大。这种新方法可以利用原本会被丢弃的器官，研究人员估计他们可以从一个捐赠的器官中为大约 75 人提供治疗。
相关故事
移植手术
给垂死病人的基因编辑猪心脏感染了猪病毒

由于众所周知且可避免的风险，首次将转基因猪心脏移植到人类体内可能已经过早结束。

“这是非常有希望的，”Valerie Gouon-Evans 说，他是一位专注于肝再生的干细胞生物学家，他没有参与这项研究，也没有加入该公司。 “我真的很高兴……这个想法正在进入诊所。”

肝脏具有独特的再生能力。把动物的肝脏切掉一半，它会重新长出来。被毒素或酒精损坏的人类肝脏通常也可以再生。但有些疾病会导致肝脏无法恢复的大范围损伤。对于这些疾病，选择的治疗方法通常是肝移植。

然而，对于身体不适的人来说，移植并不总是一种选择。这就是 Eric Lagasse 和他在 LyGenesis 的同事采取这种不同方法的原因。 Lagasse 是匹兹堡大学的干细胞生物学家，多年来一直在研究基于细胞的肝病治疗方法。大约 10 年前，他正在试验将来自健康肝脏的细胞注入小鼠患病肝脏的想法。

Lagasse 正在研究的 25 克小小鼠的肝脏很难进入，因此他和他的同事将细胞注射到患有肝病的小鼠的脾脏中。他们发现细胞能够从脾脏迁移到肝脏。为了确定它们是否可以从其他器官迁移，拉加斯的团队在小鼠体内的不同部位注射了肝细胞。

只有少数老鼠幸存下来。当拉加斯和他的同事后来对这些幸存者进行尸检时，“我非常惊讶，”他回忆道。 “我们有一个微型肝脏……淋巴结所在的位置。”
小孵化器

淋巴结是遍布全身的小豆形结构。它们在我们的免疫健康中发挥着至关重要的作用，可以制造有助于抵抗感染的细胞。他说，虽然 Lagasse 最初对肝细胞可以在淋巴结中增殖和生长感到惊讶，但这是有道理的。

淋巴结是快速分裂细胞的天然家园，即使这些细胞通常是免疫细胞。淋巴结也有良好的血液供应，可以帮助新组织的生长。

Lagasse 说，肝脏附近的淋巴结足够接近，可以接收到由患病肝脏的垂死组织发出的化学遇险信号。这些信号旨在鼓励任何剩余的健康肝组织再生，但这在严重疾病的情况下不起作用。然而，这些信号似乎确实有助于邻近淋巴结中肝组织的生长。

“这太不可思议了，”Gouon-Evans 说。 “在体内拥有这个小孵化器[可以生长器官]真是太棒了。”
拿着注射器和观察超声波机器的研究员
溶血

大约五年前，拉加斯与企业家和药物开发商迈克尔赫福德以及移植外科医生保罗丰特一起创立了 LyGenesis，以进一步推动这项技术。该团队正在探索使用淋巴结来生长新的胸腺、肾脏和胰腺。

但该公司的首要任务是肝脏。在过去的 10 年中，该团队的成员收集了有希望的证据，表明他们可以使用他们的方法在小鼠、猪和狗身上培育出新的微型肝脏。微型肝脏不会无限生长——身体有一个内部调节器，可以在某个时间点停止肝脏生长，这就是为什么健康的肝脏在再生时不会过度生长。
该团队对患有遗传性肝病的小鼠的研究表明，大多数注入淋巴结的细胞会留在那里，但如果有足够的健康肝组织剩余，一些细胞会迁移到肝脏。这些迁移的细胞可以帮助剩余的肝组织再生和愈合。发生这种情况时，淋巴结中新的微型肝脏会缩小，从而使肝脏组织的总量保持平衡，Lagasse 说。

其他研究集中在猪和狗的肝脏血液供应被转移，导致器官死亡。将肝细胞注入动物的淋巴结最终将挽救它们的肝功能。

例如，在猪研究中，该团队首先通过手术将六只动物的血液供应从肝脏转移。一旦猪从手术中恢复过来，研究小组就会将健康的肝细胞注入它们的淋巴结。剂量范围从三个淋巴结注射的 3.6 亿个细胞到 18 个淋巴结的 18 亿个细胞。

在几个月内，所有的动物似乎都从肝损伤中恢复过来。测试表明他们的肝功能有所改善。当团队后来对动物进行尸检时，淋巴结中的新器官看起来非常像微型健康肝脏，每个肝脏的大小约为典型成人肝脏的 2%。其他研究表明，治疗需要大约三个月的时间才能产生显着的益处。

“随着时间的推移，淋巴结会完全消失，剩下的是一个高度血管化的微型肝脏，它通过帮助过滤动物的血液供应来支持天然肝脏的功能，”赫福德说。 “这正是我们现在寻求在人类身上做的事情。”
新的人类肝脏

LyGenesis 的团队现在将在 12 名不符合肝移植条件的终末期肝病成人中试验他们的治疗方法。患有这种疾病的人患有慢性肝功能衰竭，随着时间的推移会恶化。肝细胞死亡，健康组织被疤痕组织取代。结果，通常由肝脏过滤的有害物质（如氨）会在血液中积聚。当肝脏停止制造有助于血液凝结的物质时，人们很容易流血和瘀伤。患有这种疾病的人也有患糖尿病、感染和肝癌的风险。

在这种情况下，通常建议人们进行肝移植，但没有足够的捐赠肝脏可供使用。在美国等待肝移植的人中约有 10% 将在被分配器官之前死亡。 Fontes 说，许多患有严重疾病的人身体不适，无法接受如此严重的手术。

该系统以前用于使被切断的猪的大脑恢复循环，现在可以恢复其他重要器官中细胞的某些功能

“你把身体最大的器官取出来，”他说。 “你把人打开，你抬起肋骨。”对于身体虚弱、生病、血液凝固不良的人来说，这是一个危险的过程。

LyGenesis 的团队正在采取一种侵入性较小的方法。健康的肝细胞将通过内窥镜输送——一根从喉咙向下输送的管子。该管将由超声波引导，当它到达目标淋巴结时，外科医生将能够直接通过它注射细胞。

细胞本身将来自被拒绝的供体肝脏——已经捐赠但不能使用的器官。有时，当捐赠者被宣布脑死亡时，肝脏不再健康到不能移植到另一个人身上，Fontes 说。但是，尽管整个器官无法使用，“你仍然可以使用这些细胞，”他说。

“使用这些原本被丢弃的器官来帮助患者……是革命性的，”Gouon-Evans 说。

Hufford 说，由于每次治疗只需要少量细胞，LyGenesis 的团队理论上应该能够从一个肝脏为 75 人或更多人提供足够的治疗。

临床试验将测试治疗的安全性，并在志愿者中寻找健康益处。第一个接受者将接受一毫升剂量的约 5000 万个细胞。

第二名志愿者将在 7 天后接受相同的剂量——让医疗团队有一周的时间来检查是否存在任何潜在问题。一旦四名志愿者接受了最低剂量，另外四名志愿者将总共将 1.5 亿个细胞注射到三个淋巴结中。最后四名志愿者将在五个淋巴结中注射 2.5 亿个细胞。如果一切按计划进行，这最后四个人除了他们原来的器官外，最终还会有五个迷你肝脏。

与猪研究中使用的细胞相比，这些细胞数量很少，因此可能需要几个月的时间才能看到仅获得 1.5 亿个细胞的人的改善，Lagasse 说。
但他相信，随着时间的推移，即使是少量的细胞也可以帮助治疗肝脏疾病。 “我的观点是一个细胞就足够了，”他说。 “如果你留出足够的时间，那个细胞就会膨胀、生长和繁殖，最终产生异位肝脏。”

试验志愿者将受到密切监视。研究人员将评估血液样本中肝功能改善的迹象，并将跟踪能量、认知和一般生活质量方面的任何潜在改善。 “每位患者都要接受一整年的研究，”赫福德说。 “我们希望在不到两年的时间内完成。”

因为他们正在接受其他人的细胞，所以所有志愿者都需要服用免疫抑制剂，以阻止他们的免疫系统在他们的余生中拒绝他们新的微型肝脏，就像接受移植供体器官的人一样。

但 LyGenesis 最近宣布与 iTolerance 合作，该公司开发技术以消除对基于药物的免疫系统抑制的需求。与该公司相关的研究人员一直在用接受新胰腺细胞治疗糖尿病的猴子测试他们的方法。赫福德希望有一天它可以在肝细胞注射的同时在人身上进行试验，尽管它还没有准备好。

如果肝脏治疗有效，LyGenesis 计划试验其他细胞，并可能生长其他器官。 “我们已经能够培养异位肾脏和异位胸腺......以及胰腺β细胞，以帮助[调节]患有糖尿病的动物的血糖水平，”他说。 Gouon-Evans 说，该公司的方法也可用于将类器官——实验室培养的微小的、类似器官的细胞团块——植入人体。

“该计划刚刚起步，”赫福德说。
杰西卡·哈姆泽卢

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This company is about to grow new organs in a person for the first time

A volunteer with severe liver disease will soon undergo a procedure that could lead them to grow a second liver.
By

    Jessica Hamzelouarchive page

August 25, 2022


In the coming weeks, a volunteer in Boston, Massachusetts, will be the first to trial a new treatment that could end up creating a second liver in their body. And that’s just the start—in the months that follow, other volunteers will test doses that could leave them with up to six livers in their bodies.

The company behind the treatment, LyGenesis, hopes to save people with devastating liver diseases who are not eligible for transplants. Their approach is to inject liver cells from a donor into the lymph nodes of sick recipients, which can give rise to entirely new miniature organs. These mini livers should help compensate for an existing diseased one. The approach appears to work in mice, pigs, and dogs. Now we’ll find out if it works in people.

If it does work, the treatment could be revolutionary. Donor organs are in short supply, and many of those donated can’t be used—for example, sometimes the tissue is too damaged. The new approach can make use of organs that would otherwise have been discarded, and the researchers reckon they can get treatments for around 75 people from a single donated organ.
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“It’s very promising,” says Valerie Gouon-Evans, a stem-cell biologist with a focus on liver regeneration, who is not involved in the research or with the company. “I’m really happy … this idea is getting into the clinic.”

Livers have a unique ability to regenerate. Cut away half an animal’s liver, and it will grow back. Human livers damaged by toxins or alcohol can usually regrow too. But some diseases can cause extensive damage from which the liver can’t recover. For these diseases, the treatment of choice is usually a liver transplant.

Transplants aren’t always an option for people who are very unwell, however. That’s why Eric Lagasse and his colleagues at LyGenesis have taken this different approach. Lagasse, a stem-cell biologist at the University of Pittsburgh, has spent years researching cell-based treatments for liver disease. Around 10 years ago, he was experimenting with the idea of injecting cells from healthy livers into diseased ones in mice.

It is difficult to access the livers of small, 25-gram mice, which Lagasse was studying, so instead he and his colleagues injected the cells into the spleens of mice with liver disease. They found that the cells were able to migrate from the spleen to the liver. To find out if they could migrate from other organs, Lagasse’s team injected liver cells at various sites in the mice’s bodies.

Only a small number of mice survived. When Lagasse and his colleagues later performed autopsies on those survivors, “I was very surprised,” he recalls. “We had a mini liver present … where the lymph node would be.”
Little incubators

Lymph nodes are small, bean-shaped structures found throughout the body. They play a crucial role in our immune health, making cells that help fight infections. And while Lagasse was initially surprised that liver cells could multiply and grow in lymph nodes, it makes sense, he says.

Lymph nodes are natural homes for rapidly dividing cells, even if those are usually immune cells. Lymph nodes also have a good blood supply, which can aid the growth of new tissue.

And the lymph nodes near the liver are close enough to receive chemical distress signals sent out by the dying tissue of a diseased liver, says Lagasse. These signals are meant to encourage any remaining healthy liver tissue to regenerate, but this doesn’t work in cases of severe disease. However, the signals do appear to help along the growth of liver tissue in neighboring lymph nodes.

“It’s incredible,” says Gouon-Evans. “Having this little incubator in the body [that can grow organs] is just amazing.”
researcher holding a syringe and watching an ultrasound machine
LYGENESIS

Around five years ago, Lagasse, along with entrepreneur and drug developer Michael Hufford and transplant surgeon Paulo Fontes, founded LyGenesis to take the technology further. The team are exploring the use of lymph nodes to grow new thymuses, kidneys, and pancreases.

But the company’s priority is livers. Over the last 10 years, members of the team have collected promising evidence that suggests they can use their approach to grow new mini livers in mice, pigs, and dogs. The mini livers don’t grow indefinitely—the body has an internal regulator that stops liver growth at a certain point, which is why healthy livers don’t overshoot when they regenerate.

The team’s research in mice with a genetic liver disorder has shown that most of the cells injected into a lymph node will stay there but some will migrate to the liver, providing there is enough healthy liver tissue remaining. These migrating cells can help the remaining liver tissue regenerate and heal. When this happens, the new mini liver in the lymph node will shrink, keeping the total amount of liver tissue in balance, says Lagasse.

Other studies have focused on pigs and dogs that have the blood supply to the liver diverted, causing the organ to die. Injecting liver cells into the animals’ lymph nodes will eventually rescue their liver function.

In the pig study, for example, the team first surgically diverted the blood supply away from the liver in six animals. Once the pigs had recovered from surgery, the team injected healthy liver cells into their lymph nodes. The doses ranged from 360 million cells injected across three lymph nodes to 1.8 billion cells across 18 lymph nodes.

Within a couple of months, all the animals appeared to show recovery from their liver damage. Tests suggested their liver function had improved. And when the team later performed autopsies on the animals, the new organs in the lymph nodes looked very much like miniature healthy livers, each up to around 2% of the size of a typical adult liver. Other studies suggest it takes around three months for the treatment to have significant benefits.

“Over time, the lymph node disappears entirely, and what you’re left with is a highly vascularized miniature liver that is supporting the function of the native liver by helping to filter the animal’s blood supply,” says Hufford. “That’s precisely what we’re seeking to do now in humans.”
New human livers

The team at LyGenesis will now trial their treatment in 12 adults with end-stage liver disease who are not eligible for liver transplants. People with this disorder have chronic liver failure that worsens over time. Liver cells die, and healthy tissue is replaced with scar tissue. As a result, harmful substances that are normally filtered by the liver, like ammonia, build up in the blood. When the liver stops making substances that help blood to clot, people can bleed and bruise easily. People with the disease are also at risk of diabetes, infections, and liver cancer.

Liver transplants are often recommended for people in this situation, but there are not enough donated livers to go around. Around 10% of people waiting for a liver transplant in the US will die before being allocated an organ. And many people with severe disease are too unwell to undergo such a serious operation, says Fontes.

The system, previously used to return circulation to severed pigs’ brains, can now restore some functions of cells in other vital organs

“You take the biggest organ of the body out,” he says. “You open the person wide open, you lift the ribs.” It is a risky procedure for someone who is weak and ill, with poor blood clotting.

The team at LyGenesis is taking a less invasive approach. The healthy liver cells will be delivered via an endoscope—a tube fed down the throat. This tube will be guided by ultrasound, and when it reaches the target lymph node, a surgeon will be able to inject the cells directly through it.

The cells themselves will come from rejected donor livers—organs that have been donated but can’t be used. Sometimes, by the time a donor is declared brain dead, the liver is no longer healthy enough to be transplanted into another person, says Fontes. But while the organ as a whole is unusable, “you can still use the cells,” he says.

“Using these organs that are otherwise discarded to help patients … is revolutionary,” says Gouon-Evans.

And because they only need a small number of cells for each treatment, the team at LyGenesis should, in theory, be able to generate enough treatments for 75 or more people from a single liver, says Hufford.

The clinical trial will test the safety of the treatment and look for health benefits among the volunteers. The first recipient will receive a one-milliliter dose of around 50 million cells.

The second volunteer will receive the same dose seven days later—leaving the medical team a week-long window to check for any potential problems. Once four volunteers have received the lowest dose, a further four will have a total of 150 million cells injected into three lymph nodes. A final four volunteers will later have 250 million cells injected across five lymph nodes. If all goes to plan, these final four individuals will end up with five mini livers in addition to their original organ.

These are small numbers of cells compared with those used in the pig study, so it will likely take months to see improvements in people who have only been given 150 million cells, says Lagasse.

But in time, even low numbers of cells could help treat liver diseases, he believes. “My view is that one cell would be enough,” he says. “If you leave enough time, that cell will expand, grow, and multiply, and eventually generate an ectopic liver.”

The trial volunteers will be closely monitored. Researchers will assess blood samples for signs of liver function improvement, and will also track any potential improvements in energy, cognition, and general quality of life. “Each patient is studied for a full year,” says Hufford. “We hope to be wrapped up in just under two years.”

Because they are receiving cells from other people, all the volunteers will need to take immunosuppressant drugs that stop their immune systems from rejecting their new mini livers for the rest of their lives, just as people who receive transplanted donor organs do.

But LyGenesis recently announced a collaboration with iTolerance, a company developing technologies to do away with the need for drug-based suppression of the immune system. Researchers associated with the company have been testing their approach in monkeys that have received new pancreatic cells to treat diabetes. Hufford hopes that it might one day be trialed in people alongside the liver-cell injections, although it isn’t ready yet.

If the liver treatment works, LyGenesis plans to trial other cells, and potentially grow other organs. “We’ve been able to grow ectopic kidneys and an ectopic thymus… and pancreatic beta cells to help [regulate the blood sugar levels of] animals with diabetes,” he says. The company’s approach could also be useful for implanting organoids—tiny lab-grown, organ-like clumps of cells—into people, says Gouon-Evans.

“The program is just getting off the ground,” says Hufford.
by Jessica Hamzelou