Innovative Gene Therapy Offers New Hope for Alagille Syndrome Patients

Researchers from Baylor College of Medicine, UMass Chan Medical School, and Cincinnati Children's Hospital Medical Center have developed a groundbreaking treatment for Alagille syndrome, a rare genetic disorder affecting multiple organs, notably causing serious liver problems that often lead to liver failure. Currently, the primary definitive treatment is liver transplantation, which involves significant risks, long waiting periods, and lifelong immunosuppressive medication. The new approach utilizes targeted gene therapy to improve bile duct development, offering a promising alternative.

In their recent study published in Gastroenterology, the team demonstrated that a single injection of AAV-mediated gene therapy in mouse models significantly enhanced liver health by promoting bile duct formation, reducing liver scarring, and improving overall liver structure—even after initial signs of damage had appeared. Remarkably, the therapy was effective when administered after liver damage was evident, suggesting potential for reversing disease progression rather than merely preventing it.

Alagille syndrome affects approximately 1 in 30,000 individuals. It is characterized by a deficit in bile ducts within the liver, leading to bile buildup and subsequent liver damage. The current standard involves delaying disease advancement via supportive care and, ultimately, liver transplantation for severe cases. However, the limitations of transplantation highlight an urgent need for innovative, less invasive therapies.

The team focused on the gene Sox4, which plays a role in biliary duct development. Interestingly, reducing Sox4 levels in mouse livers improved bile duct formation, counter to expectations. Further analysis revealed that Sox4 expression was elevated in both mouse models and human patients with Alagille syndrome. Using adeno-associated viral vectors, researchers silenced Sox4 specifically in liver cells, resulting in increased R bile ducts, decreased inflammation, and extended liver function into adulthood.

This gene therapy approach offers a promising avenue for reversing liver damage associated with Alagille syndrome, without the significant risks tied to transplantation. Moreover, the safety demonstrated in healthy mice suggests that it could be viable for broader application. Future research aims to evaluate safety at the molecular level and conduct clinical trials to assess the therapy's efficacy in humans.

Dr. Hamed Jafar-Nejad emphasizes that this strategy could radically change the treatment paradigm, potentially providing a long-term solution that may eliminate the need for transplants and dramatically improve quality of life for patients with this challenging condition.

Source: Medical Xpress