Language
English
Publication Date
10-1-2025
Journal
Gastroenterology
DOI
10.1053/j.gastro.2025.04.033
PMID
40446945
PMCID
PMC12354214
PubMedCentral® Posted Date
5-28-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Background & aims: In patients with Alagille syndrome (ALGS), bile duct paucity often leads to severe cholestatic phenotypes for which liver transplantation remains the only definitive treatment. No Food and Drug Administration-approved mechanism-based strategies exist to enhance biliary development in ALGS or other diseases with bile duct paucity. We aimed to identify a therapeutic target to address this unmet need.
Methods: Preclinical ALGS mouse models lacking 1 copy of Jag1 with or without conditional deletion of 1 or both copies of Sox9 were used. Sox4 levels were reduced genetically or with adeno-associated virus 8 (AAV8) vectors driving a Sox4-silencing sequence. Liver histology, biliary tree ink injection, serum chemistry, RNAscope (on mouse and human livers), mouse liver single-cell RNA-sequencing, and reanalysis of published human liver bulk RNA-sequencing were performed.
Results: Conditional removal of 1 copy of Sox4 in mouse liver significantly improved the ALGS liver phenotypes in a Sox9-dependent manner. An increase in Sox4/SOX4 expression in early postnatal Jag1-heterozygous mouse livers and ALGS patient livers was observed. single-cell RNA-sequencing revealed the appearance of an intermediate hepatobiliary cluster co-expressing Sox4 and Sox9 in Jag1-heterozygous livers. AAV8-mediated Sox4 knockdown, ubiquitously or driven by the hepatocyte-specific thyroxine-binding globulin promoter, led to long-term improvement of ALGS liver phenotypes upon injection at postnatal day 1. AAV8 injection at postnatal day 15-after the appearance of liver necrosis-led to the incorporation of some transduced cells into bile ducts and phenotypic improvement.
Conclusions: Preclinical studies provide proof of principle for postnatal AAV-mediated Sox4 knockdown in thyroxine-binding globulin+ cells as a therapeutic approach for ALGS liver disease.
Keywords
Animals, Disease Models, Animal, Dependovirus, Jagged-1 Protein, Humans, Phenotype, Liver, SOXC Transcription Factors, Alagille Syndrome, Mice, SOX9 Transcription Factor, Genetic Vectors, Gene Silencing, Genetic Therapy, Mice, Knockout, Cholestasis, Gene Therapy, JAG1, Notch Signaling
Published Open-Access
yes
Recommended Citation
Fox, Duncan; Xie, Jun; Burwinkel, Jennifer L; et al., "Adeno-Associated Virus-Mediated Silencing of Sox4 Leads to Long-Term Amelioration of Liver Phenotypes in Mouse Models of Alagille Syndrome" (2025). Faculty, Staff and Students Publications. 7131.
https://digitalcommons.library.tmc.edu/baylor_docs/7131