A team of researchers at Baylor College of Medicine, UMass Chan Medical School and Cincinnati Children's Hospital Medical Center has developed a new treatment that could change the outlook for patients with Alagille syndrome. The condition affects multiple organs, including the liver where it often leads to liver failure.
Currently, the condition has no definitive treatments other than liver transplant, but the team's study published in Gastroenterology shows that in mouse models of the syndrome a single injection of gene therapy can significantly improve liver health and bile duct development - even after liver damage has already begun.
"Alagille syndrome is a genetic disease that affects about 1 in 30,000 individuals. The hallmark of the condition is a significant decrease in the number of ducts that transport the bile out of the liver," said corresponding author, Dr. Hamed Jafar-Nejad, professor of molecular and human genetics at Baylor. "Consequently, the flow of bile from the liver stops or slows, leading to bile buildup that in time causes liver damage. Current treatments focus on delaying disease progression."
The only option to restore a functional biliary system in Alagille syndrome is liver transplantation but it comes with significant risks, long waiting times and lifelong medication to keep transplant rejection in check. This makes the search for new therapies especially urgent.
In the current study, the researchers focused on a gene called Sox4. Sox4 was reported to promote biliary duct development in cooperation with another gene called Sox9, suggesting that silencing Sox4 could worsen the symptoms in mouse models of the condition. Contrary to their expectations, they found that reducing Sox4 levels in the liver improved bile duct formation in mouse models of the syndrome.
This finding led the team to analyze gene expression data and discover that the expression of this gene is increased in livers of mouse models of Alagille syndrome and in patients with the condition.
A new treatment targeting liver cells
"We used adeno-associated viral gene therapy to deliver a small RNA molecule that silences the Sox4 gene specifically in mouse liver cells," said first author Duncan Fox, a graduate student in the Jafar-Nejad lab. "We were excited to see that one dose of the treatment led to the formation of more functional bile ducts, reduced liver scarring and inflammation, and improved overall liver structure and function into adulthood. This suggests repeated treatments might not be necessary to sustain a long-term effect."
"Importantly, the therapy worked when given after signs of liver damage had already appeared. This indicates that the treatment could not just prevent problems, it could help reverse them. The therapy didn't cause any harm in healthy mice, suggesting it could be safe for broader use," Fox said.
This study is a major step forward in the search for a cure for Alagille syndrome. More research is on the way, including safety studies and understanding how the therapy works at the molecular level, to eventually test the effectiveness of this promising therapy in clinical trials. "We have been studying Alagille syndrome for years. We are excited that our research points out the possibility that a single gene therapy injection could restore the biliary system and liver function in mouse models of the disease. This suggests the tantalizing possibility that a similar strategy might help the patients with Alagille syndrome avoid the need for a transplant, significantly improving their lives," Jafar-Nejad said.
Other contributors to this work include Jun Xie, Jennifer L. Burwinkel, Josh M. Adams, Kashish Chetal, Marzieh Keivandarian, Yaniv Faingelernt, Sanjay Subramanian, Mario F. Lopez, Anna L. Peters, Nathan Salomonis, Neda Zarrin-Khameh, Guangping Gao and Stacey S. Huppert. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, UMass Chan Medical School, and Cincinnati Children's Hospital Medical Center.
This study was supported by funds from the Department of Molecular and Human Genetics, Baylor College of Medicine; training grant T32 GM08307 and research grants R01 DK132751 and R01 NS076991 from the National Institutes of Health. Further support was provided by Cincinnati Pediatric Cell Atlas Center - CCHMC ARC, Neurovisualization Core at BCM IDDRC (U54 HD083092) and Gene Analysis and Integrative Morphology Cores at Digestive Diseases Research Core Center in Cincinnati (P30 DK078392).
