Alagille syndrome encompasses a variety of symptoms. In one child in regarding 100,000 births, a mutation in the JAG1 gene on chromosome 20 or the NOTCH2 gene on chromosome 1 triggers the liver disease out of. It often makes itself felt early on in the form of jaundice, but as it progresses, many other characteristics can indicate the disease.
Alagille Syndrome: Symptoms of Liver Disease
For a long time, the genetic disease was considered incurable. Recently, a team led by Associate Professor Duc Dong of the Stanford Burnham Prebys Medical Institute succeeded in developing a drug that aims to reverse some of the effects of the mutation in chromosomes 1 and 20. It might revolutionize previous approaches to treating the syndrome. But first you have to discover it. In addition to what has already been mentioned, the Swiss Children’s Liver Center of the Hôpitaux Universitaires Genève is also successful according to mostly due to the following symptoms:
- malformation of the heart
- Malformation of the spine (“butterfly vertebrae”)
- Malformation of the iris (“embryotoxon”)
- characteristic face shape
- kidney problems
- small body size
They are sometimes caused by or are side effects of the liver having a reduced number of bile ducts. This also leads to “an accumulation of so-called ‘conjugated’ bilirubin in the blood,” according to the article by the Children’s Liver Center.
“Needle Towards Healing”
With their findings, the Dong, his colleagues in the Proceedings of the National Academy of Sciences published, they might significantly advance the treatment of liver disease. “Alagille Syndrome is widely recognized as an incurable disease, but we believe we are on the way to changing that,” quoted SciTechDaily the leader of the research group. “Our goal is to advance this drug into clinical testing, and our results demonstrate its efficacy for the first time.”
Roberta Smith, President of the Alagille Syndrome Alliance, also has high hopes for the team’s work. “We have long supported Duc’s work and have come to know him as a dedicated scientist who is passionate regarding moving the needle toward healing.”
How does the new drug work?
The drug called NoRA1 activates the so-called Notch signaling pathway. This is a widespread transduction pathway that enables cells to respond to external signals. The so-called Notch receptors help control some basic biological processes in the human body. In addition to liver disease, they therefore also play an important role in a large number of other diseases.
The mutations that cause Alagille syndrome sometimes lead to a reduction in Notch signaling. This in turn causes poor growth, but also poor regeneration of the bile ducts in the liver. In animal experiments, NoRA1 was already effective and improved not only the signaling pathways but also the regeneration and repopulation of duct cells in the liver. Damage to the organ regressed and the survival rate of affected animals increased.
“The liver is known for its great regenerative capacity, but most children with Alagille syndrome lack this capacity due to impaired Notch signaling,” explains first author Chengjian Zhao, a postdoctoral fellow in Dong’s laboratory. “Our research suggests that boosting Notch signaling with a drug may be enough to restore the liver’s normal regenerative potential.”
Quellen: Hôpitaux Universitaires Genève; SciTechDaily; „Regenerative failure of intrahepatic biliary cells in Alagille syndrome rescued by elevated Jagged/Notch/Sox9 signaling“ (2022, Proceedings of the National Academy of Sciences)
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