Advances in gene therapy for Lafora disease: Intravenous recombinant adeno‐associated virus‐mediated delivery of EPM2A and EPM2B genes

Background: Lafora disease is a rare and fatal form of progressive myoclonus epilepsy that typically manifests in late childhood, presenting with seizures and progressive neurological decline. It is caused by mutations in EPM2A or EPM2B genes, encoding laforin and malin, which form a complex that regulates glycogen metabolism and mitigates cellular stress. Loss of function in either gene leads to the accumulation of Lafora bodies, insoluble polyglucosan aggregates that contribute to neurodegeneration. Methods: We previously demonstrated the efficacy of gene therapy using intracerebroventricular delivery of rAAV2/9 vectors expressing EPM2A or EPM2B in mouse models of Lafora disease. Building on these findings, we investigated the therapeutic and translational potential of a less invasive approach using intravenous delivery of rAAV2/9P31 vectors, which efficiently cross the blood-brain barrier. Gene delivery was performed at presymptomatic stages in Epm2a-/- and Epm2b-/- mice. Results: Intravenous gene therapy with rAAV2/9P31 vectors carrying EPM2A or EPM2B reversed neuropathological features of the disease, restored neuronal excitability and synaptic plasticity, and effectively prevented Lafora body formation. The therapeutic outcomes were comparable or superior to those achieved with intracerebroventricular administration. Long-term evaluation revealed no evidence of hepatotoxicity or immunogenicity. Conclusion: Our results support intravenous rAAV2/9P31-mediated gene therapy as a promising, less invasive, and safe treatment strategy for Lafora disease, with strong potential for clinical translation.