AAV-mediated PLA2G6 gene replacement for PLAN/NBIA2A: preclinical rationale and challenges for c.109C>T (p.Arg37Ter)

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.