Cerebellar Astrocyte Transduction as Gene Therapy for Megalencephalic Leukoencephalopathy
Angela Sánchez1,2, Belén García-Lareu1, Meritxell Puig1,2
1Department of Biochemistry and Molecular Biology and Institute of Neurosciences, Edifici H, Universitat Autònoma de Barcelona, E-08193, Bellaterra, Spain.
Abstract:
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder belonging to the group of vacuolating leukodystrophies. It is characterized by megalencephaly, loss of motor functions, epilepsy, and mild mental decline. In brain biopsies of MLC patients, vacuoles were observed in myelin and in astrocytes surrounding blood vessels. There is no therapy for MLC patients, only supportive treatment. We show here a preclinical gene therapy approach for MLC using the Mlc1 knock-out mouse. An adeno-associated virus coding for human MLC1 under the control of the glial fibrillary acidic protein promoter was injected in the cerebellar subarachnoid space of Mlc1 knock-out and wild-type animals at 2 months of age, before the onset of the disease, as a preventive approach. We also tested a therapeutic strategy by injecting the animals at 5 months, once the histopathological abnormalities are starting, or at 15 months, when they have progressed to a more severe pathology. MLC1 expression in the cerebellum restored the adhesion molecule GlialCAM and the chloride channel ClC-2 localization in Bergmann glia, which both are mislocalized in Mlc1 knock-out model. More importantly, myelin vacuolation was extremely reduced in treated mice at all ages and correlated with the amount of expressed MLC1 in Bergmann glia, indicating not only the preventive potential of this strategy but also its therapeutic capacity. In summary, here we provide the first therapeutic approach for patients affected with MLC. This work may have also implications to treat other diseases affecting motor function such as ataxias.
Insights
Gene therapy successfully treated a rare genetic disorder, megalencephalic leukoencephalopathy with subcortical cysts (MLC), in mice. This preclinical study offers hope for a potential treatment for MLC patients and other motor function disorders.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder characterized by megalencephaly, motor dysfunction, and epilepsy.
- Current treatments for MLC are limited to supportive care, with no specific therapies available.
- Vacuoles in myelin and astrocytes are key pathological hallmarks of MLC.
Purpose of the Study:
- To evaluate a preclinical gene therapy approach for Megalencephalic leukoencephalopathy with subcortical cysts (MLC).
- To investigate both preventive and therapeutic potential of gene therapy for MLC.
- To assess the efficacy of adeno-associated virus-mediated gene delivery of MLC1.
Main Methods:
- Adeno-associated virus carrying human MLC1 was administered via cerebellar subarachnoid injection in Mlc1 knock-out and wild-type mice.
- Injections were performed at different ages (2, 5, and 15 months) to test preventive and therapeutic strategies.
- Restoration of GlialCAM and ClC-2 localization in Bergmann glia was assessed.
Main Results:
- MLC1 gene therapy restored the localization of GlialCAM and ClC-2 in Bergmann glia of treated mice.
- Myelin vacuolation was significantly reduced in treated Mlc1 knock-out mice across all tested ages.
- The reduction in vacuolation correlated with the level of expressed MLC1, demonstrating dose-dependent efficacy.
Conclusions:
- This study presents the first preclinical gene therapy approach for Megalencephalic leukoencephalopathy with subcortical cysts (MLC).
- The gene therapy demonstrated both preventive and therapeutic potential, significantly reducing key pathological features.
- This approach may offer a future treatment for MLC and potentially other motor function disorders like ataxias.
