‘incurable’ liver disease may have met its match

alagille syndrome is a rare genetic disorder that prevents the formation and regeneration of the liver’s bile ducts.

by dave yasvinski

published jan 05, 2023

3 minute read

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3 minute read

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alagille syndrome is incurable. a new drug might change that.

alagille syndrome affects between one in 30,000 to one in 40,000 newborns. getty

a new study has found that a single drug may be capable of reversing the effects of a currently incurable form of liver disease. the research, which appears in the journal proceedings of the national academy of sciences, showed the potential of this medication to address the devastating effects of alagille syndrome, a rare genetic disorder that prevents the formation and regeneration of the liver’s bile ducts. without proper drainage, the ensuing buildup of bile can damage the liver and lead to a range of other problems, according to sickkids hospital.

the disorder, which is estimated to affect between one in 30,000 to one in 40,000 newborns, has a 75 per cent mortality rate by late adolescence in the absence of a liver transplant.

“alagille syndrome is widely considered an incurable disease but we believe we’re on the way to changing that,” said duc dong, the study’s lead researcher and an associate professor at sanford burnham prebys graduate school in california. “we aim to advance this drug into clinical trials and our results demonstrate its effectiveness for the first time.”

the new drug, known as nora1, works by activating the notch pathway, a cell-to-cell signalling system that helps coordinate many fundamental biological processes. the notch pathway, which is present in almost all animals, has a hand in alagille syndrome and several other diseases. children born with this form of liver disease possess a genetic mutation that leads to a reduction in notch signalling, which impedes liver duct growth and regeneration.

in tests on animals with the same genetic mutation, nora1 was found to increase notch signalling and trigger the regeneration and repopulation of duct cells in the liver. it effectively reversed damage to the liver and increased the likelihood of survival. the team is now testing the drug on miniature livers created in the lab using stem cells from patients with alagille syndrome.

“the liver is well known for its great capacity to regenerate but this doesn’t happen in most children with alagille syndrome because of compromised notch signaling,” said chengjian zhao, first author of the study and a postdoctoral researcher in dong’s lab. “our research suggests that nudging the notch pathway up with a drug could be enough to restore the liver’s normal regenerative potential.”

dong is also creating a startup company to accelerate the drug’s progression to clinical trials and, hopefully, provide relief to patients with the syndrome and a host of other, more prevalent diseases — including some forms of cancer. “instead of forcing the cells to do something unusual, we are just encouraging a natural regenerative process to occur,” dong said. “i’m optimistic that this will be an effective therapeutic for alagille syndrome.”

with no cure and few effective treatments, the results of the study offer hope for patients of a chronic condition that produces a host of symptoms, including itchy or yellow skin, delayed growth, kidney disease and enlarged spleens.

“duc and his team continue to do thrilling research on alagille syndrome and these breakthroughs certainly offer hope for families living with this very complicated and complex disorder,” said roberta smith, president of the alagille syndrome alliance.

“we have been longtime supporters of duc’s work and have come to know him as a driven, dedicated scientist who is passionate about moving the needle one step closer toward a cure.”

dave yasvinski is a writer with healthing.ca

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