Base Editing (ABE8e) for PLA2G6 c.2356G>A (p.Glu786Lys)

Base Editing (ABE8e) via AAV9 delivery is a rationale-driven therapeutic strategy for PLA2G6-associated neurodegeneration (PLAN) / Neurodegeneration with brain iron accumulation 2A (NBIA2A) targeting the PLA2G6 c.2356G>A (p.Glu786Lys) variant (Pathogenic, missense variant, 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: CNS. Therapeutic goal: Correct the PLA2G6 p.Trp783Ter loss-of-function mutation at chr22:38112233 (GRCh38) to restore functional iPLA2-VI activity and halt or slow neurodegeneration in PLAN/NBIA2A.. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Medium, immunogenicity High (AAV pre-existing immunity).

1. Molecular basis: PLA2G6 NM_003560.4(PLA2G6):c.2356G>A (p.Glu786Lys) is classified as Pathogenic (ClinVar variation ID 998023). Molecular consequence: missense variant, intron variant. Protein change: E554K, E560K, E608K, E732K, E786K, P223Q, P45Q. 2. Epidemiology: PLA2G6-associated neurodegeneration (PLAN/NBIA2A) is an ultra-rare, autosomal recessive neurodegenerative disorder with an estimated prevalence around 1 per million, presenting as a spectrum that includes infantile neuroaxonal dystrophy (onset 6–36 months), atypical childhood-onset neuroaxonal dystr 3. Standard of care: There is no disease-modifying or curative treatment for PLAN/NBIA2A. Management is supportive and multidisciplinary, including pharmacologic treatment of spasticity and seizures (e.g., baclofen, antiepileptic drugs), dopaminergic agents for parkinsonism, management of dystonia sometimes with deep br 4. Pipeline: No interventional clinical trials or approved medicinal products specifically targeting PLA2G6-associated neurodegeneration were identified in ClinicalTrials.gov or Orphanet/EMA databases. NBIA-focused programs (e.g., iron chelation, symptomatic interventions) are in early-stage development (mainly 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 PLA2G6 c.2356G>A (p.Glu786Lys) 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. Delivery to CNS tissue remains a major translational bottleneck. Current vectors have limited transduction efficiency in these compartments.
4. Long-term durability, off-target genome-wide effects, and immunogenicity in the target patient population require thorough preclinical and clinical evaluation.