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A groundbreaking study led by researchers at University College London (UCL) has identified an existing drug that can prevent liver cell death caused by high levels of ammonia, potentially offering new hope for patients with liver disease. The research, published in Science Advances, highlights the role of ammonia in damaging mitochondria, the energy powerhouses of cells, and presents a promising treatment strategy using the drug YAQ-005.
The Impact of Ammonia on Liver Cells
Hyperammonemia, the buildup of ammonia in the bloodstream, is a well-known contributor to brain dysfunction in patients with liver disease. However, this study is the first to demonstrate that ammonia directly harms liver cells by damaging their mitochondria, leading to a dangerous cycle of cellular breakdown.
Professor Rajiv Jalan, the senior author of the study from the UCL Institute for Liver & Digestive Health, explained, “Ammonia is usually cleared from the body via the urea cycle in the liver. In patients with liver disease, ammonia accumulates and can cause severe complications, including brain dysfunction. Until now, the precise mechanism behind this damage remained unclear.”
The study revealed that ammonia increases the levels of two proteins, RIPK1 and RIPK3, which contribute to mitochondrial damage and trigger a form of cell death that leads to liver scarring. The research also identified the TLR4 signaling pathway as a key player in this process, signaling the immune system and exacerbating liver injury.
A Potential Treatment for Liver Disease
Encouragingly, the researchers found that the drug YAQ-005, previously known as TAK-242, can protect mitochondria from ammonia-induced damage. By preventing mitochondrial dysfunction, the drug enables liver cells to continue converting ammonia into urea, allowing the body to excrete it safely.
YAQ-005 has been patented by UCL Business (UCLB) and licensed to the UCL spinout company Yaqrit. It is currently in phase II clinical trials for acute-on-chronic liver failure, a severe condition related to cirrhosis. Researchers believe the drug may also be effective for children with urea-cycle disorders and other genetic conditions that result in elevated ammonia levels.
In the study, two experimental drugs—RIPA-56, which blocks the RIPK1 pathway, and YAQ-005, which inhibits TLR4 activation—successfully reduced liver injury and cell death in mouse models. These findings suggest a new avenue for therapeutic intervention in chronic liver disease, for which targeted drugs are currently lacking.
Dr. Annarein Kerbert, first author of the study, stated, “Targeted drugs to prevent chronic liver disease progression do not yet exist. This study highlights the potential of YAQ-005 in protecting the liver from hyperammonemia-induced toxicity. Our next step is to investigate this further in clinical studies.”
Looking Ahead: Clinical Trials
A phase II clinical trial for YAQ-005 is set to begin recruiting patients with liver failure in mid-2025. This trial will be crucial in determining the drug’s effectiveness in human patients and could pave the way for a novel treatment for liver disease.
Troels Jordansen, CEO of Yaqrit, expressed optimism about the trial, saying, “We are eager to advance this innovative drug into phase II trials for acute-on-chronic liver failure. This is a serious, life-threatening condition, and there is a significant need for new treatment options.”
As research progresses, YAQ-005 may provide a much-needed breakthrough for millions of people suffering from liver disease worldwide.
Disclaimer: The information provided in this article is based on a scientific study and is intended for informational purposes only. The drug mentioned is still undergoing clinical trials and has not yet been approved for widespread medical use. Patients should consult their healthcare providers before considering any new treatment options.
