Lipid nanoparticle-encapsulated mRNA therapy corrects serum total bilirubin level in Crigler-Najjar syndrome mouse model

Crigler-Najjar syndrome is a rare disorder of bilirubin meta-bolism caused by uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) mutations characterized by hyperbilirubinemia and jaundice. No cure currently exists; treatment options are limited to phototherapy, whose effectiveness diminishes over time, and liver transplantation. Here, we evaluated the the-rapeutic potential of systemically administered, lipid nanopar-ticle-encapsulated human UGT1A1 (hUGT1A1) mRNA therapy in a Crigler-Najjar mouse model. Ugt1 knockout mice were rescued from lethal post-natal hyperbilirubinemia by photo -therapy. These adult Ugt1 knockout mice were then adminis-tered a single lipid nanoparticle-encapsulated hUGT1A1 mRNA dose. Within 24 h, serum total bilirubin levels decreased from 15 mg/dL (256 mmol/L) to <0.5 mg/dL (9 mmol/L), i.e., slightly above wild-type levels. This reduction was sustained for 2 weeks before bilirubin levels rose and returned to pre-treatment levels by day 42 post-administration. Sustained re-ductions in total bilirubin levels were achieved by repeated administration of the mRNA product in a frequency-dependent manner. We were also able to rescue the neonatal lethality phenotype seen in Ugt1 knockout mice with a single lipid nano -particle dose, which suggests that this may be a treatment mo-dality appropriate for metabolic crisis situations. Therefore, lipid nanoparticle-encapsulated hUGT1A1 mRNA may repre-sent a potential treatment for Crigler-Najjar syndrome.

Automated summary

Crigler-Najjar syndrome is a rare disorder characterized by hyperbilirubinemia and jaundice caused by UGT1A1 mutations. This study investigated the therapeutic potential of lipid nanoparticle-encapsulated hUGT1A1 mRNA therapy in a mouse model and demonstrated that it can effectively reduce bilirubin levels. The results suggest that this treatment modality may be a potential option for Crigler-Najjar syndrome.