UGT1A1 gene-augmentation rationale for c.16C>T (p.Gln6Ter)

For UGT1A1 c.16C>T (p.Gln6Ter), liver-directed gene augmentation remains the strongest mechanism-matched therapeutic direction because this very early nonsense allele is expected to abolish normal UGT1A1 function, and current augmentation programs bypass the stop codon by supplying an intact hepatic transgene.

ClinVar classifies UGT1A1 c.16C>T (p.Gln6Ter) as likely 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 demonstrated in the phase 1/2 GNT0003 study, where systemic AAV-UGT1A1 delivery reduced bilirubin and markedly lowered phototherapy burden in Crigler-Najjar syndrome (PMID:37585628; NCT:NCT03466463). Because p.Gln6Ter is an extremely upstream stop-gain allele in a classic loss-of-function disease, transgene supplementation is more directly supported than codon-specific rescue strategies at the current stage of development.

The clinical evidence is disease-level rather than specific to p.Gln6Ter, so this should be read as a mechanism-based interpretation rather than proof of allele-specific response. Treatment feasibility still depends on liver status, vector immunity, dose-related safety, and access. Re-dosing limitations and longer-term durability remain unresolved for the AAV platform.