PLA2G6-associated neurodegeneration (PLAN) / Neurodegeneration with brain iron accumulation 2A (NBIA2A)

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. 4. 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.

For PLA2G6 c.109C>T (p.Arg37Ter), a pathogenic nonsense variant causing complete loss of calcium-independent phospholipase A2 group VI (iPLA2β), AAV-mediated CNS gene replacement is the most rationally targeted therapeutic strategy. iPLA2β is critical for membrane phospholipid remodeling and mitochondrial membrane homeostasis in neurons. The p.Arg37Ter truncation at residue 37 eliminates the entire catalytic and regulatory domains, producing no functional enzyme. AAV9-PLA2G6 delivered intrathecally or systemically could restore iPLA2β expression in the degenerating neurons of the cerebellum, basal ganglia, and cortex.

PLA2G6-associated neurodegeneration (PLAN) encompasses infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy, and adult-onset dystonia-parkinsonism with brain iron accumulation (NBIA2). iPLA2β catalyzes the release of fatty acids from membrane phospholipids, playing essential roles in membrane remodeling, mitochondrial function, and calcium signaling. The Pla2g6-knockout mouse develops progressive cerebellar ataxia, neuroaxonal spheroids, and brain iron accumulation, recapitulating human PLAN. The PLA2G6 cDNA (~2.4 kb) fits easily within AAV packaging capacity. Preclinical AAV9-PLA2G6 gene therapy in Pla2g6-KO mice has shown rescue of neurological phenotypes, including improved motor function, reduced neuroaxonal spheroid formation, and extended survival when delivered neonatally. Brain iron accumulation — a hallmark imaging finding — may reflect secondary mitochondrial dysfunction and is expected to be mitigated by restoring iPLA2β activity.

PLAN typically presents in infancy (INAD form) with rapid neurodegeneration, creating a very narrow treatment window. By the time clinical diagnosis is made (usually after 6-12 months of progressive regression), significant irreversible neuronal loss has occurred. Postnatal gene therapy may arrest progression but cannot reverse established axonal degeneration. Brain iron accumulation may have independent neurotoxic effects not directly addressable by gene replacement alone — iron chelation (deferiprone) has been explored as adjunctive therapy but with limited efficacy. AAV9 CNS distribution after systemic or intrathecal delivery may not adequately reach the cerebellum and globus pallidus, which are most severely affected. No clinical trial for PLA2G6 gene therapy has been initiated. The adult-onset dystonia-parkinsonism form of PLAN has a fundamentally different disease tempo and may represent a distinct therapeutic opportunity with a wider treatment window.