Ammonia buildup kills liver cells but preented using drug

High Levels of Ammonia Kill Liver Cells by Damaging The Mitochondria That Power The Cells. But this can be prevented an existing drug due to start clinical trials, finds a New Study in Mice Led by Researchers from UCL.

The Study, published in Science Advancesis the first to observe that the buildup of ammonia (hyperammonemia) can ham liver cells, and the first to describe how this damage occurs in mouse models that are clinically relevant for human.

Hyperammonemia is Known to Cause Brain Dysfunction in Those With Liver Disease, But 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. This can lead to problems, including in the brain.

“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 – Act AS The Powerhouse of Cells. 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 Hospitalized with an episode of Confusion or Comu 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 the Their Job of Converting Ammonia Into Urea So That It Can Be Excredited AS URINE (A PROCESS CALLED THE UREA CYCLE).

YAQ-005, Which has Been Pated by UCL Business (UCLB), The Commercialization Company for UCL, and Licensed to UCL Spinout Company Yaqrit, is Currently in a Phase II Clinical Trial for Acute-Chronic Liver Failure, A Condition Related To Cirrhose.

The Authors Believe That the Drug May Also Be Effective for Children with Urea-Cycle Disorders and Phher Genetic Diseases That Lead to Increased Ammonia by Causing Mitochhondial Dysfunction (Hepatic Mitochhopathies).

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 Mitochhondial Damage and A Dangeous Form of Cell Death That Not Only Harms The Liver also also Organs, including the Imamune System.

There was also increased activity in the tlr4 Signaling Pathway, Which Alerts the Imamune System When Pathoges Are Detected and Is Known To Induce The Production of Ripk1 Proteins.

Increases in ripk1 and ripk3 corresponded to incredited Liver Scarring and Liver Cell Death, Proving That Ammonia Directly Causes Liver Injury for the First Time.

The Team then Administred Two Drugs, Ripa-56 to Block the Ripk1 Pathway and Yaq-005 to Prevent The Activation of the Tlr4 Pathway, Which Led to Significant Reduction 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 Center, Said, “Targeded Drugs to Prevent Chronic Liver Disease Progression Currently Do not exist. In Protecting The Liver From the Toxic Effects of Hyperammonemia.

Phase II Trial Clinical for Yaq-005 is due to begin Recruiting Patients with Liver Failure in Mid-2025, Which Provide the First Proof of Concept for This Treatment In Human Patients.

Troels Jordansen, CEO of Yaqrit, added, “We Are Looking Forward to Advance This Innovative Drug, Licensed from UCL, Into Phase II Trials in Acute-Chronic Liver Failure. This is a complicated Life-Threading Condition and There is an urgent need for new Approaches. “