Gene therapy shows promise for Alagille liver disease: Mouse study
Treatment potentially effective for patients already showing liver damage
The use of an experimental, one-time gene therapy in a mouse model of Alagille syndrome increased the number of bile ducts — tubes that carry the digestive fluid bile from the liver — and resulted in long-term liver function improvements in the animals, a study showed.
The researchers noted that liver-related benefits were seen in mice given the therapy only after liver damage was established.
These findings suggest gene therapy could potentially be of benefit for people with the rare genetic disease.
“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,” Hamed Jafar-Nejad, MD, the study’s senior author and a professor at Baylor College of Medicine in Texas, said in a university news story. “This suggests the tantalizing possibility that a similar strategy might help the patients with Alagille syndrome avoid the need for a [liver] transplant, significantly improving their lives.”
The study, “AAV-mediated silencing of Sox4 leads to long-term amelioration of liver phenotypes in mouse models of Alagille syndrome,” was published in the journal Gastroenterology.
Jafar-Nejad this month won a Scholar-Innovator Award of $100,000 from the Harrington Discovery Institute to further develop the gene therapy for Alagille.
“Through Harrington’s unique model of support, we aim to accelerate … progress toward delivering new therapies to the patients who need them most,” said Seth J. Field, MD, PhD, chief scientific officer and director of Harrington’s physician-scientist programs, said in an institute press release announcing this year’s award recipients.
Reducing gene’s activity boosted bile duct formation in mice
In Alagille syndrome, mutations in one copy of either the JAG1 or NOTCH2 genes, which are involved in embryonic development, lead to a wide range of developmental abnormalities.
Intrahepatic bile duct paucity, marked by fewer bile ducts inside the liver, is Alagille’s most common complication. This results in slowed or stalled bile flow, a condition called cholestasis, and bile buildup in the liver, which can disrupt its function and lead to tissue scarring and liver failure. The bile ducts transport bile from the liver and gallbladder through the pancreas and into the small intestine.
Current Alagille treatments address the symptoms specific to each patient but not the condition’s underlying causes. A liver transplant is the sole option that can restore bile flow in Alagille. However, it comes with significant risks and requires long-term medication use.
Emerging evidence suggests that an interaction between two genes — Sox4 and Sox9 — plays a role in bile duct development. Increased levels of the SOX9 protein have been found in the blood of infants with biliary atresia, a condition characterized by blocked or absent bile ducts.
Previous work by Jafar-Nejad and others showed removing one or both copies of Sox9 from the liver of an Alagille mouse model worsened liver disease. This suggested that removing one Sox4 copy could also worsen liver disease in these mice, similar to Sox9, the team noted.
Jafar-Nejad, along with colleagues at the UMass Chan Medical School in Massachusetts and Cincinnati Children’s Hospital Medical Center in Ohio, subsequently teamed up to further investigate the role of Sox4 and Sox9 in Alagille-related liver disease.
Contrary to the team’s expectations, reducing Sox4 activity in the liver boosted bile duct formation in Alagille mice, an effect dependent on the presence of one working copy of Sox9.
Gene therapy decreased liver inflammation, improved function
When the researchers examined the livers of mice with Alagille-like disease, they found elevated activity of both Sox4 and Sox9 genes compared with the livers of healthy mice. Likewise, both genes were boosted in the liver tissue of an 11-month-old child with Alagille.
These findings prompted the team to test whether a gene therapy targeting Sox4 could effectively lessen or prevent Alagille-related liver disease. The treatment uses a modified, harmless adeno-associated virus to specifically deliver into mouse liver cells a genetic material designed to suppress the activity of the Sox4 gene.
[This] strategy could be effective in treating patients who already show a liver damage response at the time of diagnosis.
Data showed administering the gene therapy to Alagille mice shortly after birth increased the number of bile ducts, reduced liver inflammation and scarring, and improved overall liver function. No liver problems were observed when healthy mice received the same treatment.
“The therapy didn’t cause any harm in healthy mice, suggesting it could be safe for broader use,” said Duncan Fox, the study’s first author and a graduate student in the Jafar-Nejad lab.
All of the treated animals reached adulthood, compared with 60% of untreated mice, and showed a well-developed bile duct system with significantly more bile ducts and less inflammation and scarring.
“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,” Fox said. “This suggests repeated treatments might not be necessary to sustain a long-term effect.”
Similar benefits were also seen when Alagille mice received the therapy only after the appearance of liver damage, according to the researchers, indicating the “strategy could be effective in treating patients who already show a liver damage response at the time of diagnosis.”
Fox added that “this indicates that the treatment could not just prevent problems, it could help reverse them.”
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