Alagille syndrome is known as a fatal genetic disorder that affects various organs and systems, most notably the liver. Currently, there is no known cure for it but scientists have now identified one that is likely to be effective.
The newly developed drug, called NoRA1, targets the Notch pathway, a cell-level signaling system in the body that is important for many vital biological systems, including the proper maintenance of the liver, reports Al-Rai daily.
The genetic mutation behind Alagille syndrome causes a decrease in Notch signaling, which then leads to impaired bile duct growth and regeneration, causing bile buildup and liver damage.
Zebrafish are often used in scientific research on human diseases, thanks to our extensive knowledge of their genome, the similarities in genes, and the ease with which their evolution can be observed. In the most recent research, NoRA1 was shown to enhance Notch signaling in zebrafish (the zebrafish [Danio rerio] is a freshwater fish belonging to the minnow family [Cyprinidae[ of the order Cypriniformes. Native to South Asia) with similar gene mutations to those found in children diagnosed with the disease.
The duct cells were stimulated to grow and regenerate as healthy liver tissue does, reversing liver damage in zebrafish. The chances of survival of the zebrafish participating in the study were increased by applying the treatment. In fact, just one dose of NoRA1 four days after fertilization was enough to achieve a three-fold improvement in survival rates.
“The liver is known for its great ability to regenerate, but this does not happen in most children with Alagille syndrome because of compromised Notch signaling,” says molecular biologist Chengjian Zhao of the Stanford Burnham Prebys Medical Discovery Institute in California. Our research indicates that driving the Notch pathway into a drug could be sufficient to restore the liver’s natural ability to regenerate.”
One of the benefits of the drug is that it targets processes in the body that should occur naturally. This bodes well when it comes to testing this on actual people in the future, should the treatment progress to clinical trials.
“Instead of forcing the cells to do something unusual, we’re just encouraging a natural regeneration process to happen, so I’m optimistic that this will be an effective treatment for Alagille syndrome,” says molecular biologist Duc Dong, also of Stanford Burnham Prebys Institute for Medical Discovery.
There is scope for NoRA1 to help with other common diseases as well, and it is critical to the Notch pathway for the proper functioning of daily biological processes. For now, though, the focus is on how to help treat this rare liver disease.
More than 4,000 babies are born each year with Alagille syndrome, and liver transplants are often needed. Without a transplant — and a shortage of donors — there is a 75 percent mortality rate in the late teens.
Currently, the researchers are working on lab-grown mini livers, using stem cells derived from Alagille syndrome patients to test the NoRA1 drug further.
The research has been published by the Proceedings of the National Academy of Sciences (PNAS).
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