UGT1A1 gene-replacement rationale for c.1069C>T (p.Gln357Ter)

For UGT1A1 c.1069C>T (p.Gln357Ter), liver-directed gene replacement remains the strongest mechanism-matched therapeutic direction because this nonsense allele is expected to cause severe loss of enzymatic function, and current UGT1A1 augmentation programs bypass the stop codon by supplying a functional hepatic transgene.

ClinVar classifies UGT1A1 c.1069C>T (p.Gln357Ter) as pathogenic. In Crigler-Najjar models, liver-directed AAV-UGT1A1 vectors produced durable bilirubin correction and survival benefit (PMID:27722180; PMID:29448836). Human translation has now been shown in the phase 1/2 GNT0003 study, where systemic AAV-UGT1A1 delivery reduced bilirubin levels and substantially lowered phototherapy dependence in Crigler-Najjar syndrome (PMID:37585628; NCT:NCT03466463). Because p.Gln357Ter is a true stop-gain allele in a classic loss-of-function disease, gene augmentation is more directly supported than codon-specific rescue strategies at the current stage of development.

The direct clinical evidence is disease-level rather than specific to p.Gln357Ter, so this is a mechanism-based interpretation rather than proof of allele-specific response. AAV treatment feasibility still depends on hepatic status, dose-related safety, preexisting immunity, and access. Re-dosing limitations and long-term durability remain unresolved across the platform.