Brao, AlejandroSánchez, ÁngelaRodríguez, IrinaRey, Javier delLope Piedrafita, SilviaPrat, EstherNunes Martínez, VirginiaChillón, MiguelEstévez Povedano, RaúlBosch, Assumpció2025-06-302025-06-302025-03-061525-0016https://hdl.handle.net/2445/221916Megalencephalic 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.15 p.application/pdfengcc by-nc-nd (c) Brao, Alejandro et al., 2025http://creativecommons.org/licenses/by-nc-nd/3.0/es/Teràpia genèticaEdema cerebralCerebelGene therapyCerebral edemaCerebelluminfo:eu-repo/semantics/article2025-06-06info:eu-repo/semantics/openAccess40051162