Antisense oligonucleotide-mediated upregulation of ameliorates liver disease phenotypes in a mouse model of Alagille syndrome.

Alagille syndrome (ALGS) is a rare genetic disorder that affects multiple organ systems, especially the liver, leading to life-threatening complications. In most cases, ALGS is caused by haploinsufficient mutations in the gene, resulting in impaired liver bile duct development during early childhood. Therefore, increasing JAG1 protein levels in ALGS patients offers a potential therapeutic approach. In this study, we designed antisense oligonucleotides (ASOs) targeting the mRNA to enhance translation through different mechanisms. We found that certain ASOs targeting the upstream open reading frame (uORF) increased JAG1 protein levels in various cell lines and ALGS patient-derived cells. Optimized ASOs also increased Jag1 protein levels in normal mouse liver for up to 2-fold, accompanied by elevated levels of cleaved Notch1 protein, suggesting that the increased Jag1 protein was functionally active. Importantly, ASO treatment increased Jag1 protein in mouse model. When newborn mice were treated with ASO, improved bile duct development was observed, along with trends of reduced plasma bile acids, bilirubin, and triglyceride levels, implying improved liver function. Together, these results suggest that ASO-induced JAG1 upregulation may provide a promising therapeutic opportunity for ALGS patients, especially when treated at an early age.