Researchers develop new approach to treat acute liver failure

August 3, 2012

Acute liver failure is a life-threatening disease, characterized by a sudden, massive death of liver cells. Unfortunately, few treatment options exist, especially for advanced-stage liver failure. As a last resort a liver transplant may be the only remaining option. Now the physician Dr. Junfeng An of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Dr. Stefan Donath, a specialist in internal medicine and cardiology, also of the MDC and Helios Klinikum Berlin-Buch, have developed a new treatment approach based on a mouse model. In their current study published in Hepatology, the liver failure was reversed and the mice recovered completely. The researchers hope to soon be able to test their new approach in clinical trials with patients.

According to an estimate published in a 2011 issue of the "Deutsche Ärzteblatt", a professional journal for German physicians, between 200 and 500 patients suffer from acute in Germany each year. Poisoning from mushrooms or drugs is one of the main causes of this serious liver disease. In Southern Europe, Africa and Asia an acute infection with the hepatitis B virus is considered to be the most important cause.

For their treatment approach the two researchers utilized the recently discovered protein ARC (apoptosis repressor with caspase recruitment domain), which serves as the body's own survival switch. ARC is expressed in heart and skeletal muscle and in the brain, but not in the liver. In 2006 Dr. Donath showed that apoptosis is the cause for the death of myocardial during heart failure, but that ARC stopped the myocardial cells from being destroyed.

Apoptosis protects the body from diseased or defective cells. In tumor cells apoptosis is deactivated, allowing the cancer cells to proliferate uncontrollably. Cancer researchers are therefore striving to utilize apoptosis to develop a treatment. They are looking for ways to reactivate apoptosis to drive the proliferating cancer cells into programmed suicide. However, in acute liver failure the problem is not too little but rather too much apoptosis. Physicians administer drugs in an attempt to halt the destruction of the cells, but only with modest success.

Now Dr. Donath and his colleagues have fused ARC to a noninfectious fragment of the human immunodeficiency virus (HIV), called TAT for short. The researchers used TAT as a shuttle to transfer this survival-switch construct into the liver. Mice with acute liver failure were given an intravenous or intraperitoneal injection with the construct. "Within just a few minutes the fusion protein TAT-ARC reached the liver of the animals and immediately began to take effect. ARC was able to stop the apoptosis of the , and all of the animals completely recovered," Dr. Donath said. "ARC is very fast acting, and this is a huge advantage, because in an emergency there is not much time for treatment. And when the massive damage is over, the liver is quite capable of regenerating itself. In addition, ARC reaches other organs via the bloodstream, not only the liver. "Moreover," he pointed out, "since TAT-ARC only has to be administered for a short time, a cancer risk can be largely excluded."

During their studies, the researchers also discovered a new active mechanism of ARC, which apparently is responsible for the protective function of this protein in the liver. It inhibits the activity of a molecule (JNK), which is activated in immune cells of the liver and causes abnormal processes, whereby another molecule (TNF alpha) is released that causes the liver cells to die. ARC thus protects the liver cells from destruction. The researchers hope to soon be able to test their new approach in clinical trials with patients.

Dr. Donath and the MDC have patented the fusion protein TAT-ARC for the indication of . The research project was funded by the MDC Pre-Go-Bio project, an internal project fund of the MDC that supports the transfer of diagnostic or therapeutic procedures obtained in basic research into clinical applications.

Explore further: Cellular target may aid in drug therapies for acute liver failure

More information: TAT-ARC protein transduction rescues mice from fulminant liver failure, Hepatology, doi:101002/hep.25697 ; Vol. 56, No. 2, August 2012

Related Stories

Cellular target may aid in drug therapies for acute liver failure

June 3, 2011
(Medical Xpress) -- New insights into the biological mechanisms that contribute to acute liver failure could help scientists better understand—and eventually treat—a broader spectrum of liver diseases, according ...

Scientists identify key protein linked to acute liver failure

September 7, 2011
New research from the Keck School of Medicine of the University of Southern California (USC) may help prevent damage to the liver caused by drugs like acetaminophen and other stressors.

Pioneering liver treatment cures British baby

November 15, 2011
British doctors on Tuesday said they had cured a baby boy of a life-threatening liver disease using a pioneering treatment in which cells are injected into the abdomen.

Recommended for you

Two Group A Streptococcus genes linked to 'flesh-eating' bacterial infections

September 22, 2017
Group A Streptococcus bacteria cause a variety of illnesses that range from mild nuisances like strep throat to life-threatening conditions including pneumonia, toxic shock syndrome and the flesh-eating disease formally known ...

Ecosystem approach makes urinary tract infection more treatable

September 22, 2017
The biological term 'ecosystem' is not usually associated with urinary tract infections, but this should change according to Wageningen scientists.

Residents: Frontline defenders against antibiotic resistance?

September 22, 2017
Antibiotic resistance continues to grow around the world, with sometimes disastrous results. Some strains of bacteria no longer respond to any currently available antibiotic, making death by infections that were once easily ...

Individualized diets for irritable bowel syndrome better than placebo

September 21, 2017
Patients with irritable bowel syndrome who follow individualized diets based on food sensitivity testing experience fewer symptoms, say Yale researchers. Their study is among the first to provide scientific evidence for this ...

Superbug's spread to Vietnam threatens malaria control

September 21, 2017
A highly drug resistant malaria 'superbug' from western Cambodia is now present in southern Vietnam, leading to alarming failure rates for dihydroartemisinin (DHA)-piperaquine—Vietnam's national first-line malaria treatment, ...

A dose of 'wait-and-see' reduces unnecessary antibiotic use

September 21, 2017
Asking patients to take a 'wait-and-see' approach before having their antibiotic prescriptions filled significantly reduces unnecessary use, a University of Queensland study has shown.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.