New drug shows promise for the treatment of ‘incurable’ fatal syndrome

Alagille syndrome is a rare genetic disease that causes problems with several body systems, including the liver, and can be fatal if left untreated. There is currently no therapy or cure, but researchers have found a promising option.

The newly created drug, called NoRA1, targets the Notch pathway, a cellular-level signaling system in the body that is critical for many vital biological functions, including healthy liver function.

Impaired Notch signaling is caused by the genetic mutation underlying Alagille syndrome, which in turn impairs the growth and regeneration of the bile ducts, leading to bile buildup that ultimately damages the liver.

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Scientists often use the zebrafish in human disease studies because of our deep familiarity with the genome, the similarities between its genes and those of humans, and the relative ease with which their development can be tracked.

Recent studies have shown that NoRA1 can enhance Notch signaling in zebrafish carrying the same genetic abnormalities as human children with the condition. Similar to a healthy liver, the zebrafish were able to reverse liver damage by stimulating the growth and regeneration of duct cells.

The therapy improved the zebrafish’s chances of survival during the study. The survival rate could even be increased three-fold with just one dose of NoRA1 four days after conception.

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In most children with Alagille syndrome, liver regeneration does not occur due to impaired Notch signaling Chengjian Zhaoa molecular scientist at Sanford Burnham Prebys Medical Discovery Institute in California.

“Our findings indicate that a drug that stimulates the Notch pathway may be all that is needed to restore the liver’s normal regenerative potential.” The drug is useful because it interferes with the body’s natural processes, which is what it is supposed to do.

That’s encouraging news for when the therapy hopefully moves on to human trials later. Molecular biologist Duc Dong of the Sanford Burnham Prebys Medical Discovery Institute says, “Rather than forcing the cells to do something unique, we’re just supporting a normal regenerative process, so I’m optimistic this will be a successful therapy for Alagille.” syndrome.”

Due to the fundamental importance of the Notch pathway for normal cellular functions, NoRA1 may also prove useful in the treatment of other common conditions. The potential benefits for treating this unusual liver condition are currently in the spotlight.

Each year, more than 4,000 babies are born with Alagille syndrome, necessitating liver transplants. There is a 75% mortality rate by late adolescence without transplantation, and donors are scarce. The NoRA1 medication is currently being tested in lab-grown microlivers using stem cells from patients with rheumatoid arthritis Alagille syndrome.

Even though we still have a way to go, progress is being made. Dong says, “We feel we are on our way to changing the commonly held belief that Alagille syndrome is incurable.” Our findings represent the first evidence of the drug’s effectiveness, and we hope to use them to advance it into clinical trials. The research is published in the Proceedings of the National Academy of Sciences.

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