NM_001110792.2(MECP2):c.62+2T>A

For MECP2 c.62+2T>A, a pathogenic splice donor variant that disrupts exon 1 splicing and abolishes MeCP2 protein production from the mutant allele, adenine base editing (ABE) offers a conceptually precise correction strategy. The T>A transversion at position +2 of the splice donor can be reverted by ABE (which converts A to G on the target strand, equivalent to T to C on the opposite strand) — however, reverting A back to T requires a different approach since ABE performs A-to-G, not A-to-T. Prime editing may be required for exact reversion. Nevertheless, ABE could potentially install an alternative base at this position that restores splice donor function. Rett syndrome from MECP2 mutations is particularly interesting for gene editing because X-inactivation mosaicism means ~50% of neurons express wild-type MeCP2 — correcting even a fraction of the mutant-expressing neurons could shift the mosaic balance favorably.

Adenine base editors have been successfully deployed in vivo for other neurological conditions: the PRNP base editing study (An et al., 2025, PMID: 39810005) achieved 37% editing efficiency in brain using dual AAV. For MECP2, Sinnamon et al. (2020, PMID: 32444596) demonstrated CRISPR-mediated correction of Mecp2 mutations in mouse brain organotypic cultures. The +2 position of the splice donor is part of the invariant GT dinucleotide; any base change here (T>A, T>C, T>G) disrupts splicing. To restore function, the base must be reverted to T, or potentially C (since GC at +1/+2 is a functional splice donor in some contexts). X-inactivation mosaicism in Rett syndrome means the therapeutic threshold is potentially lower than for non-mosaic diseases — even partial correction of the mutant allele in neurons expressing it could restore MeCP2 levels above the phenotypic threshold.

The primary challenge for MECP2 gene editing in Rett syndrome is the same as for gene therapy: dosage sensitivity. MeCP2 overexpression causes MECP2 duplication syndrome (severe ID, seizures, infections). Base editing must be restricted to the mutant allele — inadvertent editing of the wild-type allele on the active X chromosome could create new mutations. Allele-specific editing requires distinguishing the two alleles by sequence, which may be possible if the mutant allele contains a unique PAM-proximal SNP, but this is patient-specific and not guaranteed. For c.62+2T>A specifically, the T-to-A transversion cannot be directly corrected by ABE (A-to-G) or CBE (C-to-T) — prime editing would be needed for exact reversion, and prime editing in post-mitotic neurons via AAV is still in early development with lower efficiency than base editing. Delivery to sufficient neurons across the brain via intrathecal or IV AAV remains a distribution challenge. No MECP2 gene editing therapy has entered clinical trials.