Adenine base editing for PAH c.1161C>A (p.Tyr387Ter): LNP-delivered ABE as one-dose metabolic cure for classical PKU

For PAH c.1161C>A (p.Tyr387Ter), a nonsense variant in exon 11 that abolishes phenylalanine hydroxylase activity, adenine base editing (ABE) delivered via lipid nanoparticles (LNPs) to hepatocytes represents a potentially curative one-dose approach. The variant creates a TAA stop codon (c.1161C>A changes UAC→UAA on the mRNA); on the antisense strand, the target adenine in the TAG complement can be converted to guanine by ABE (A→G on antisense = T→C on sense), reverting the stop codon to a sense codon. This strategy leverages the established hepatotropism of LNPs and avoids the immunogenicity concerns of AAV-based delivery, while potentially achieving durable correction through editing of long-lived hepatocytes.

Brooks et al. (HGG Adv 2024; PMID:37922902) demonstrated that mRNA-LNP delivery of an adenine base editor with an optimized guide RNA achieved sufficient PAH editing in mouse hepatocytes to fully normalize blood phenylalanine levels within 48 hours of a single intravenous dose in c.1222C>T humanized PKU mice. While that study targeted the R408W variant, the ABE platform is adaptable to other PAH stop codons where the target adenine falls within the ABE editing window (positions 4-8 of the protospacer). Villiger et al. (Nat Med 2021; PMID:33707775) showed that AAV-delivered ABE corrected the PAH c.835T>C variant in Pah-enu2 mice with sustained phenylalanine normalization over 26 weeks. For p.Tyr387Ter specifically, ClinVar classifies this variant as Pathogenic. Tyr387 is located in the catalytic domain of PAH near the active site; restoration of any amino acid compatible with PAH folding at this position would be therapeutic — ABE would convert the stop to a glutamine (TAG→CAG on antisense), arginine, or other amino acid depending on the editing window, and in silico tolerance prediction suggests multiple substitutions at position 387 retain enzymatic activity.

The specific base editing strategy for c.1161C>A (p.Tyr387Ter) has not been experimentally validated — this analysis extrapolates from the proven ABE-LNP platform applied to other PAH variants. The editing product amino acid (determined by the specific A-to-G conversion within the editing window) must be verified as compatible with PAH enzymatic function; not all amino acid substitutions at position 387 may retain activity. LNP delivery achieves high liver tropism but editing efficiency in non-human primates is lower than in mice — clinical translation requires demonstration of sufficient hepatocyte editing (estimated >5-10% correction needed for metabolic normalization based on enzyme kinetics). LNP immunogenicity after repeated dosing is a concern if the initial editing efficiency is subtherapeutic, though ideally a single dose achieves sufficient correction. Off-target editing (both DNA off-targets and RNA editing by ABE deaminase) requires thorough safety characterization. For compound heterozygous patients with one copy of p.Tyr387Ter and a different PAH variant on the other allele, correcting one allele may be sufficient given the recessive inheritance of PKU — but this depends on the residual activity of the second allele.