AAV-UGT1A1 replacement is a strong disease-level fit for UGT1A1 c.1069C>T (p.Gln357Ter)

For UGT1A1 c.1069C>T (p.Gln357Ter), a pathogenic nonsense variant consistent with complete loss of bilirubin UDP-glucuronosyltransferase activity, liver-directed gene replacement remains a strong disease-level therapeutic fit because it bypasses the stop codon and restores enzyme function without allele-specific repair. The real translational question is not whether this null allele matches the platform, but whether durable bilirubin control can be maintained in infants and young children where hepatocyte turnover challenges episomal AAV persistence.

ClinVar classifies c.1069C>T (p.Gln357Ter) as pathogenic. Preclinical translational work with optimized AAV-UGT1A1 vectors showed durable bilirubin correction in Crigler-Najjar models, establishing the biological plausibility of liver-directed gene addition for null UGT1A1 alleles (PMID:27722180; PMID:29448836). In humans, the phase 1/2 GNT0003 program reported clinically meaningful bilirubin lowering and major phototherapy reduction after systemic AAV delivery in Crigler-Najjar syndrome, supporting the platform as the most advanced gene-therapy route currently in the clinic (PMID:37585628; NCT:NCT03466463). For a stop-gain like p.Gln357Ter, that rationale is more direct than any speculative codon-specific rescue strategy.

The evidence is disease-level rather than specific to p.Gln357Ter. Durability, pediatric redosing, immune barriers, and competition with liver transplantation remain the central unresolved issues. This means the post should be read as a platform-fit interpretation for a severe loss-of-function UGT1A1 allele, not as proof that this exact nonsense variant predicts a distinct or superior response profile.