Base Editing (ABE8e) for PAH c.865G>A (p.Gly289Arg) in Phenylketonuria

Base Editing (ABE8e) via LNP delivery is a rationale-driven therapeutic strategy for Phenylketonuria targeting the PAH c.865G>A (p.Gly289Arg) 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 PAH Arg408Trp and similar loss-of-function variants in hepatocytes to restore sufficient PAH activity and normalize systemic phenylalanine levels, preventing neurotoxicity.. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Low, immunogenicity Low.

1. Molecular basis: PAH NM_000277.3(PAH):c.865G>A (p.Gly289Arg) is classified as Pathogenic (ClinVar variation ID 458082). Molecular consequence: missense variant. Protein change: G289R. 2. Epidemiology: Global birth prevalence of PAH-deficient PKU is ~1:16,000–1:24,000 newborns, with higher rates in certain countries (e.g., up to ~1:4,000 in parts of the Middle East) and routine newborn screening in most high-income regions. 3. Standard of care: Lifelong low-phenylalanine diet with medical foods started in the neonatal period, with adjunctive pharmacologic options in subsets of patients including sapropterin or sepiapterin (for BH4-responsive PAH deficiency) and pegvaliase enzyme substitution for adults with uncontrolled Phe. 4. Pipeline: Multiple liver-directed AAV gene-addition therapies for PAH are in preclinical to Phase I/II trials; mRNA/LNP and in vivo base-editing approaches correcting common PAH variants have shown metabolic cure in mouse models but have not yet entered human gene-editing trials as of the latest evidence. 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 PAH c.865G>A (p.Gly289Arg) 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.