first approach to gene therapy for MLC disease in preclinical models

A study involving the U750 CIBERER led by Raúl Estévez from the University of Barcelona-IDIBELL and IP of the Physiology And Pathology Of The Glia-Neurona Functional Relation group at the Institute of Neurosciences UB offers the first approach to gene therapy to treat the rare disease megalencephalic leukoencephalopathy with subcortical cysts (MLC) in murine models.

Representation of the correction achieved in the murine model of MLC disease. This model (Mlc1 – / -) shows vacuolization in the cerebellum and the GlialCAM and ClC-2 proteins are delocalized. After administering adeno-associated viruses expressing Mlc1 in astrocytes, the vacuolization is reduced and the location of these proteins is recovered.

So far, there is only supportive treatment, but no curative therapy, for patients with MLC, a rare genetic disease characterized by megalencephaly, loss of motor functions, epilepsy, and average mental retardation. Vacuoles in myelin and astrocytes surrounding blood vessels have been observed in biopsies of the brain of MLC patients. The authors of this work, in which the group led by Assumpció Bosch at the UAB and the CIBER of Neurodegenerative Diseases (CIBERNED) have also participated, have been able to improve MLC disease preclinically using the Mlc1 knockout mouse as a model , one of the genes that causes the disease.

The researchers have injected adenoassociated viruses into this mouse model that express Mlc1 under the control of the GFAP promoter in the subarachnoid space of the cerebellum and reduce the pathology both preventively and once the disease has developed, even in animals with a very pathological condition. severe. This research, published in Neurotherapeutics, is the first therapeutic approach for patients affected with MLC and may have implications for the treatment of other diseases that affect motor functions such as ataxias. Virginia Nunes, a researcher at IDIBELL and the University of Barcelona, ​​has also participated in carrying out this study.

Reference article

“Cerebellar Astrocyte Transduction as Gene Therapy for Megalencephalic Leukoencephalopathy”. Angela Sánchez, Belén García-Lareu, Meritxell Puig, Esther Prat, Jesús Ruberte, Miguel Chillón, Virginia Nunes, Raul Estévez & Assumpció Bosch. Neurotherapeutics (2020) https://doi.org/10.1007/s13311-020-00865-y

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