1. Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome.
- Author
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Luoni M, Giannelli S, Indrigo MT, Niro A, Massimino L, Iannielli A, Passeri L, Russo F, Morabito G, Calamita P, Gregori S, Deverman B, and Broccoli V
- Subjects
- Animals, Disease Models, Animal, Gene Expression physiology, Gene Expression Regulation, Genetic Therapy methods, Mice, Transgenic, Transgenes genetics, Brain metabolism, Methyl-CpG-Binding Protein 2 genetics, Mutation genetics, Rett Syndrome genetics
- Abstract
Rett syndrome is an incurable neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles since MECP2 is expressed throughout the brain and its duplication leads to severe neurological conditions as well. Herein, we use the AAV-PHP.eB to deliver an instability-prone Mecp2 (i Mecp2 ) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral Mecp2 transgene, limits supraphysiological Mecp2 protein levels. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic Mecp2 mutant mice significantly improved locomotor activity, lifespan and gene expression normalization. Remarkably, PHP.eB-iMecp2 administration was well tolerated in female Mecp2 mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male Mecp2 mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of i Mecp2 provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain., Competing Interests: ML, SG, MI, AN, LM, AI, LP, FR, GM, PC, SG, BD, VB No competing interests declared, (© 2020, Luoni et al.)
- Published
- 2020
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