Study of the Week: Scientists May Have Found a New Therapy for Alagille Syndrome

Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.


This week’s study is…

Regenerative failure of intrahepatic biliary cells in Alagille syndrome rescued by elevated Jagged/Notch/Sox9 signaling

We previously published about this research in a story titled “Scientists Discover Potential New Treatment for Alagille Syndrome” which can be found here. The study was originally published in the research journal PNAS. You can read the abstract of the study here

This research team was affiliated with the Sanford Burnham Prebys Medical Discovery Institute in California, USA.

What Happened?

Alagille syndrome is rare disorder that has impacts on multiple systems and organs, but the liver in particular is impacted. As a result, this disorder is potentially lethal. There are limited treatment options outside of a small number of medications or organ transplants. However, a recent study appears to have found a new treatment that could revolutionize the treatment of Alagille syndrome. The researchers are calling the new medication NoRA1.

This treatment is designed to act on pathway called Notch. It’s a signaling system that is important for a lot of the body’s functions, including maintaining the health and integrity of the liver. In fact, it’s crucial to the liver’s ability to heal and regenerate. The mutation responsible for Alagille syndrome interferes with Notch signals. This results in poor liver regeneration and insufficient growth of the bile ducts. As a result, Alagille syndrome often have a backup of excess bile, leading to liver damage. 

The researchers evaluated the impact of NoRA1 in zebrafish (Danio rerio) that were genetically modified with mutations comparable to those that are found in the disease. The found that a single dose of NoRA1, administered four days following egg fertilization, saw the survival rates of these zebrafish increase by three times. As the treatment restores a natural process that is supposed to be happening in the body, researchers are optimistic that it will be well-tolerated in human patients.

While the scientists are excited about the potential for treating Alagille syndrome with NoRA1, it could potentially be useful in other conditions too in which Notch signaling is impacted. Overall, the research team has concluded that they may have discovered a new method for the treatment of this rare disease.

About Alagille Syndrome

Alagille syndrome is a rare genetic disorder that has impacts on a variety of organs, including the kidneys, liver, and heart. Signs and symptoms become noticeable early in life. It can vary widely in severity, and may hardly produce symptoms in some cases. The syndrome is caused by mutations of the JAG1 or NOTCH2 genes. Symptoms include jaundice, cholesterol deposits on the skin, itching, pale stools, numerous heart defects, butterfly shaped bones on the spine, eye defects, and narrowed pulmonary arteries. Treatment includes several medications to improve bile flow and surgery to repair heart defects. In the most severe cases, a liver transplant may be necessary. Prompt treatment is paramount upon diagnosis of Alagille syndrome. In some cases, if left untreated, the complications of the syndrome can be fatal. There is a serious need for more treatment options for this disease. To learn more about Alagille syndrome, click here.

Why Does it Matter?

While the severity and outcomes of Alagille syndrome can vary greatly, the grim reality is that the patients that are most severely impacted by the disease may not respond to current treatment options, leading to an early death. The findings of this study, however are a cause for genuine hope among the Alagille syndrome community.

“Instead of forcing the cells to do something unusual, we are just encouraging a natural regenerative process to occur, so I’m optimistic that this will be an effective therapeutic for Alagille syndrome.” – Duc Dong, molecular biologist, Sanford Burnham Prebys Medical Discovery Institute

While NoRA1 is still far from fully proven as an effective therapy in humans, the results from this study are certainly promising.

“Our research suggests that nudging the Notch pathway up with a drug could be enough to restore the liver’s normal regenerative potential.” – Chengjian Zhao, molecular biologist, Sanford Burnham Prebys Medical Discovery Institute

The scientists are continued to study NoRA1 by testing it on tiny livers propagated in the lab with stem cells from Alagille syndrome patients. 

“Alagille syndrome is widely considered an incurable disease, but we believe we’re on the way to changing that…We aim to advance this drug into clinical trials, and our results demonstrate its effectiveness for the first time.” – Dong


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