Base Editing (ABE8e) for RPE65 c.11+5G>A in RPE65-associated Leber congenital amaurosis (RPE65-LCA)

Base Editing (ABE8e) via AAV delivery is a rationale-driven therapeutic strategy for RPE65-associated Leber congenital amaurosis (RPE65-LCA) targeting the RPE65 c.11+5G>A variant (Pathogenic, intron 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: Eye/Retina. Therapeutic goal: Correct or functionally replace biallelic loss-of-function RPE65 variants in retinal pigment epithelium to restore the visual cycle and improve vision.. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Medium, immunogenicity High (AAV pre-existing immunity).

1. Molecular basis: RPE65 NM_000329.3(RPE65):c.11+5G>A is classified as Pathogenic (ClinVar variation ID 98825). Molecular consequence: intron variant. 2. Epidemiology: RPE65-LCA is an ultra-rare autosomal recessive inherited retinal dystrophy causing severe early-onset vision loss and progressive retinal degeneration; inherited retinal diseases overall affect about 1 in 4000 people with substantial national economic burden. 3. Standard of care: Historically, management was limited to supportive and low-vision care. Luxturna (voretigene neparvovec), an AAV2-based subretinal RPE65 gene augmentation therapy, is now approved for patients with confirmed biallelic RPE65 mutations and viable retinal cells but is costly and access-limited. 4. Pipeline: Luxturna is approved with Phase I/III data; additional ocular gene therapies (e.g., RPGR, ABCA4, ND4) and the in vivo CRISPR therapy EDIT-101 for CEP290-LCA10 illustrate a rapidly evolving pipeline relevant to future RPE65-targeted gene-editing approaches. 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 RPE65 c.11+5G>A 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.