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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/221916
Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts
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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an ultrarare, infantile-onset leukodystrophy characterized by white matter edema for which there is no treatment. More than 75% of diagnosed cases result from biallelic loss-offunction mutations in the astrocyte-specific gene MLC1, leading to early-onset macrocephaly, cerebellar ataxia, epilepsy, and mild cognitive decline. To develop a gene therapy for MLC, we administered an adeno-associated viral vector capable of crossing the murine blood-brain barrier, delivering the human MLC1 cDNA under the control of a human astrocyte-specific promoter, to 10-month-old Mlc1-'- mice. We observed long-term astrocyte-driven expression of MLC1 up to 1 year after viral vector administration in all brain areas analyzed. Despite the late-stage intervention, in vivo magnetic resonance imaging revealed normalization of water accumulation. Notably, our therapy successfully reversed locomotor deficits in Mlc1-'- mice, as evidenced by improved performance in motor tests assessing cerebellar ataxia-like behaviors. Collectively, these findings not only demonstrate the sustained efficacy of our gene therapy but also highlight the reversibility of vacuolation and motor impairments in Mlc1-'- mice, suggesting that MLC patients could benefit from treatment even after symptom onset.
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BRAO, Alejandro, SÁNCHEZ, Ángela, RODRÍGUEZ, Irina, REY, Javier del, LOPE PIEDRAFITA, Silvia, PRAT, Esther, NUNES MARTÍNEZ, Virginia, CHILLÓN, Miguel, ESTÉVEZ POVEDANO, Raúl, BOSCH, Assumpció. Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts. _Molecular Therapy_. 2025. Vol. 33, núm. 4, pàgs. 1434-1448. [consulta: 25 de febrer de 2026]. ISSN: 1525-0016. [Disponible a: https://hdl.handle.net/2445/221916]