Base Editing (ABE8e) for UGT1A1 c.1124C>T (p.Ser375Phe) in Crigler-Najjar syndrome type I

Base Editing (ABE8e) via LNP delivery is a rationale-driven therapeutic strategy for Crigler-Najjar syndrome type I targeting the UGT1A1 c.1124C>T (p.Ser375Phe) variant (Pathogenic, missense variant). The editing system (ABE8e-nSpCas9 (adenine base editor)) converts the pathogenic A back to G on the target strand, restoring the wild-type codon. Target tissue: Liver. Therapeutic goal: Correct loss-of-function UGT1A1 mutations in hepatocytes at the UGT1A1 locus to restore bilirubin glucuronidation and prevent kernicterus. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Low, immunogenicity Low.

1. Molecular basis: UGT1A1 NM_000463.3(UGT1A1):c.1124C>T (p.Ser375Phe) is classified as Pathogenic (ClinVar variation ID 12267). Molecular consequence: missense variant. Protein change: S376F, S107F, S372F, S374F, S375F. 2. Epidemiology: Ultra-rare autosomal recessive congenital liver disease characterized by severe unconjugated hyperbilirubinemia presenting in the neonatal period; precise prevalence is unknown but considered extremely low. 3. Standard of care: Intensive, often daily phototherapy from infancy to delay kernicterus; orthotopic liver transplantation is currently the only curative treatment option. 4. Pipeline: Liver-directed AAV8 gene therapy delivering functional UGT1A1 (e.g., AT342) is in Phase I/II clinical development; additional AAV programs are in early-phase trials, while in vivo gene-editing approaches remain preclinical. 5. ABE clinical validation: ABE8e (Richter et al. 2020, Nat Biotechnol) achieves ~1.7x higher editing efficiency than ABE7.10. VERVE-101 demonstrated first-in-human LNP-ABE liver editing with 55-66% PCSK9 reduction (Raal et al. 2025, NEJM). Beam Therapeutics is advancing multiple ABE programs.

1. No published data specifically correcting UGT1A1 c.1124C>T (p.Ser375Phe) with Base Editing (ABE8e); strategy is based on general principles and must be validated preclinically.
2. PAM availability and bystander base analysis for the specific genomic context have not been performed. If no canonical NGG PAM positions the target within the editing window, PAM-flexible variants (SpRY) may be needed.
3. Long-term durability, off-target genome-wide effects, and immunogenicity in the target patient population require thorough preclinical and clinical evaluation.