Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome
Open Access
- 24 March 2020
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
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 (iMecp2) 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 iMecp2 provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain.Keywords
Funding Information
- Fondazione Telethon (GGP19038)
This publication has 54 references indexed in Scilit:
- A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndromeNature Genetics, 2013
- NMDA Receptor Regulation Prevents Regression of Visual Cortical Function in the Absence of Mecp2Neuron, 2012
- Rate of de novo mutations and the importance of father’s age to disease riskNature, 2012
- MeCP2 Is Critical for Maintaining Mature Neuronal Networks and Global Brain Anatomy during Late Stages of Postnatal Brain Development and in the Mature Adult BrainJournal of Neuroscience, 2012
- Fast gapped-read alignment with Bowtie 2Nature Methods, 2012
- Adult Neural Function Requires MeCP2Science, 2011
- Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypesNature, 2010
- Direct conversion of fibroblasts to functional neurons by defined factorsNature, 2010
- Sexually Dimorphic Patterns of Episomal rAAV Genome Persistence in the Adult Mouse Liver and Correlation With Hepatocellular ProliferationMolecular Therapy, 2009
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005