Ammonia build-up kills liver cells but can be prevented using existing drug

(Press-News.org) High levels of ammonia kill liver cells by damaging the mitochondria that power the cells. But this can be prevented using an existing drug due to start clinical trials, finds a new study in mice led by researchers from UCL.

The study, published in Science Advances, is the first to observe that build-up of ammonia (hyperammonaemia) can harm liver cells and describe how this damage occurs in mouse models that are clinically relevant for humans.

Hyperammonaemia is known to cause brain dysfunction in those with liver disease, but a lack of effective treatments for the condition has meant the prognosis for patients is often poor.

Professor Rajiv Jalan, senior author of the study from the UCL Institute for Liver & Digestive Health, said: “Ammonia is a toxin that is usually cleared from the body via the urea cycle, which takes place in the liver. We know that liver disease patients accumulate ammonia and that this can lead to problems, including in the brain. But until now we didn’t understand exactly how this occurred.

“In this study we’ve demonstrated that ammonia kills liver cells by damaging the mitochondria, which apart from their role in clearing ammonia from the body also act as the powerhouse of cells. It’s a vicious cycle where the more the mitochondria are damaged, the more ammonia builds up, which snowballs into complete system breakdown.”

Of the 100 million people in the world with cirrhosis (scarring of the liver), about three million are hospitalised with an episode of confusion or coma that is associated with elevated ammonia levels in blood and brain tissues, with 10-15% of these expected to die within three months of the episode.

In promising news for these patients, the research demonstrated that an existing drug, called YAQ-005 (previously known as TAK-242), can halt damage to the mitochondria in liver cells, allowing them to do their job of converting ammonia into urea so that it can be excreted as urine (a process called the urea cycle).

YAQ-005, which has been patented by UCL Business (UCLB), the commercialisation company for UCL, and licensed to UCL spinout company Yaqrit, is currently in a phase II clinical trial for acute-on-chronic liver failure, a condition related to cirrhosis.

The authors believe that the drug may also be effective for children with urea-cycle disorders and other genetic diseases that lead to increased levels of ammonia by causing mitochondrial dysfunction (hepatic mitochondriopathies).

In the study, the researchers observed that in two mouse models, elevated levels of ammonia caused an increase in two proteins, called RIPK1 and RIPK3, which leads to mitochondrial damage and a dangerous form of cell death that not only harms the liver but also other organs, including the immune system.

There was also increased activity in the TLR4 signalling pathway, which alerts the immune system when pathogens are detected and is known to induce the production of RIPK1 proteins.

Increases in RIPK1 and RIPK3 corresponded to increased liver scarring and liver cell death, proving that ammonia directly causes liver injury for the first time.

The team then administered two drugs, RIPA-561 to block the RIPK1 pathway and YAQ-005 to prevent the activation of the TLR4 pathway, which led to significant reduction in liver injury and cell death in the mice.

Dr Annarein Kerbert, first author of the study from UCL Institute for Liver & Digestive Health and Leiden University Medical Centre, said: “Targeted drugs to prevent chronic liver disease progression currently do not exist. In this study, we have shown the potential of the drug YAQ-005 in protecting the liver from the toxic effects of hyperammonaemia. We therefore believe that this could be a potential novel therapy for disease progression in cirrhosis. Our aim is to investigate this further in proof-of-concept clinical studies.”

A phase II clinical trial for YAQ-005, which will be sponsored by Yaqrit and funded by a European Union grant, is due to begin recruiting patients with liver failure in mid-2025, which will provide the first proof of concept for this treatment in human patients.

Troels Jordansen, CEO of Yaqrit, added: “We are looking forward to advancing this innovative drug, licensed from UCL, into phase II trials in acute-on-chronic liver failure. This is a complicated life-threatening condition and there is an urgent need for new approaches.”

This research was supported by a Sheila Sherlock Postdoctoral Fellowship for Dr Kerbert, awarded by the European Association for the Study of the Liver (EASL).

Notes to Editors:

1 Though RIPA-56 was found to inhibit necroptosis (a form of cell death), it is not currently available for clinical use.

For more information, please contact:

 Dr Matt Midgley

+44 (0)20 7679 9064

m.midgley@ucl.ac.uk

Publication:

Annarein J.C. Kerbert et al. ‘Hyperammonemia induces programmed liver cell death’ is published in Science Advances and is strictly embargoed until Friday 7 March at 19:00 GMT / 14:00 ET.

DOI: https://doi.org/10.1126/sciadv.ado1648

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