RT Journal Article
T1 Gene therapy for Lafora disease in the Epm2a-/- mouse model
A1 Zafra Puerta, Luis
A1 Iglesias-Cabeza, Nerea
A1 Burgos, Daniel F
A1 Sciaccaluga, Miriam
A1 González Fernández, Juan
A1 Bellingacci, Laura
A1 Canonichesi, Jacopo
A1 Sánchez-Martín, Gema
A1 Costa, Cinzia
A1 Sánchez, Marina P
A1 Serratosa, José M
AB 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.
PB ELSEVIER
YR 2024
FD 2024-07-03
LK https://hdl.handle.net/20.500.14352/113467
UL https://hdl.handle.net/20.500.14352/113467
LA eng
NO Zafra-Puerta L, Iglesias-Cabeza N, Burgos DF, Sciaccaluga M, González-Fernández J, Bellingacci L, Canonichesi J, Sánchez-Martín G, Costa C, Sánchez MP, Serratosa JM. Gene therapy for Lafora disease in the Epm2a-/- mouse model. Mol Ther. 2024 Jul 3;32(7):2130-2149. doi: 10.1016/j.ymthe.2024.05.032. Epub 2024 May 24. PMID: 38796707; PMCID: PMC11286821.
DS Docta Complutense
RD 29 abr 2025