Existing Drug Shows Promise in Preventing Liver Cell Death Caused by Ammonia Buildup

Recent research has revealed that high levels of ammonia can lead to severe damage and death of liver cells by impairing their mitochondria. This study, conducted by researchers at University College London (UCL), indicates that the adverse effects of ammonia buildup, known as hyperammonemia, can be mitigated by a drug that is already in the clinical trial phase.

The findings, published in the journal Science Advances, mark the first instance of researchers identifying how ammonia accumulation harms liver cells in mouse models that are relevant for human health. While hyperammonemia has been associated with neurological dysfunction in patients with liver diseases, effective treatments have been scarce, leading to poor patient outcomes.

Professor Rajiv Jalan from UCL's Institute for Liver & Digestive Health emphasized the significance of their discovery. Ammonia, typically cleared from the body through a process called the urea cycle in the liver, becomes problematic for individuals with liver disease as it accumulates, resulting in detrimental effects, particularly on the brain.

In this study, researchers found that ammonia is toxic to liver cells due to the damage it inflicts on mitochondria, the cellular powerhouses responsible for energy production. This damage creates a feedback loop: as mitochondrial function declines, ammonia levels rise, leading to further cell injury. Alarmingly, approximately three million of the 100 million individuals globally who suffer from cirrhosis experience episodes of confusion or coma related to elevated ammonia levels, with a significant mortality rate within three months following such episodes.

Encouragingly, the research highlighted that YAQ-005, an existing drug formerly known as TAK-242, can protect liver cells from mitochondrial damage caused by ammonia. This drug has been patented by UCL Business and is currently undergoing a Phase II clinical trial for acute-on-chronic liver failure, a condition linked to cirrhosis.

The researchers are optimistic that YAQ-005 may also benefit children suffering from urea-cycle disorders and other genetic conditions that lead to elevated ammonia levels due to mitochondrial dysfunction.

The study's findings revealed that in two mouse models, elevated ammonia led to the increased expression of proteins RIPK1 and RIPK3, which are associated with mitochondrial damage and a form of cell death detrimental not only to the liver but to the immune system as well. Additionally, heightened activity in the TLR4 signaling pathway, which signals the immune system in response to pathogens, was noted, indicating a connection between ammonia exposure and immune system activation.

To counteract the damaging effects of ammonia, the team administered two drugs in the mouse models: RIPA-56, which inhibits the RIPK1 pathway, and YAQ-005, which blocks the TLR4 pathway. The treatment resulted in a notable decrease in liver injury and cell death.

Dr. Annarein Kerbert, the first author of the study, expressed the importance of developing targeted therapies for chronic liver disease progression, which currently lack effective options. The protective effects of YAQ-005 against the toxic impacts of hyperammonemia demonstrate its potential as a novel therapeutic approach for cirrhosis management.

Recruitment for the Phase II clinical trial for YAQ-005 is anticipated to begin in mid-2025, offering the first opportunities to assess its effectiveness in human patients with liver failure. Troels Jordansen, CEO of Yaqrit, acknowledged the urgency of advancing this innovative drug, emphasizing the need for new treatment strategies for this complex and life-threatening condition.