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 at the hepatic locus to restore bilirubin conjugation and prevent kernicterus in Crigler-Najjar syndrome type I. 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: Exceptionally rare autosomal recessive disorder with incidence ~0.6-1 per 1,000,000 newborns worldwide; presents in neonates with severe unconjugated hyperbilirubinemia and high risk of kernicterus. 3. Standard of care: CN1 requires intensive, often daily, phototherapy and sometimes plasmapheresis to control bilirubin; liver transplantation is currently the only curative treatment and is recommended before irreversible neurological damage. 4. Pipeline: Multiple liver-directed UGT1A1 gene therapies are in early to pivotal clinical development. An AAV8-based UGT1A1 gene therapy (e.g., AlphaCN/GT-UGT1A1-AAV8-02, GNT-0003) is in Phase I/II with EMA PRIME designation and transitioning to pivotal trials; preclinical LNP mRNA therapies are also being mod 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.