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Lafora disease is a rare and fatal form of progressive myoclonic epilepsy typically occurring early in adolescence. The disease results from mutations in the EPM2A gene, encoding laforin, or the EPM2B gene, encoding malin. Laforin and malin work together in a complex to control glycogen synthesis and prevent the toxicity produced by misfolded proteins via the ubiquitin-proteasome system. Disruptions in either protein cause alterations in this complex, leading to the formation of Lafora bodies containing abnormal, insoluble, and hyperphosphorylated forms of glycogen. We used the Epm2a -/- knockout mouse model of Lafora disease to apply gene therapy by administering intracerebroventricular injections of a recombinant adeno-associated virus carrying the human EPM2A gene. We evaluated the effects of this treatment through neuropathological studies, behavioral tests, video-electroencephalography, electrophysiological recordings, and proteomic/phosphoproteomic analysis. Gene therapy ameliorated neurological and histopathological alterations, reduced epileptic activity and neuronal hyperexcitability, and decreased the formation of Lafora bodies. Moreover, differential quantitative proteomics and phosphoproteomics revealed beneficial changes in various molecular pathways altered in Lafora disease. Our results represent proof of principle for gene therapy with the coding region of the human EPM2A gene as a treatment for EPM2A-related Lafora disease., Competing Interests: Declaration of interests The authors report no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Lafora disease (LD) is a life-threatening autosomal recessive and progressive neurodegenerative disorder that primarily affects adolescents, resulting in mortality within a decade of onset. The symptoms of LD include epileptic seizures, ataxia, dementia, and psychosis. The underlying pathology involves the presence of abnormal glycogen inclusions in neurons and other tissues, which may contribute to neurodegeneration. LD is caused by loss-of-function mutations in either the EPM2A gene or the NHLRC1 gene. These two genes, respectively, code for laforin phosphatase and malin ubiquitin ligase, and are thought to function, as a functional complex, in diverse cellular pathways. One of the major pathways affected in LD is glycogen metabolism; defects here lead to abnormally higher levels of glycogen and its hyperphosphorylation and aggregation, resulting in the formation of Lafora inclusion bodies. Currently, there is no effective therapy for LD. Studies, particularly from animal models, provide distinct insights into the fundamental mechanisms of diseases and potential avenues for therapeutic interventions. The purpose of this review is to present a comprehensive overview of our current knowledge regarding the disease, its genetics, the animal models that have been developed, and the therapeutic strategies that are being developed based on an understanding of the disease mechanism.