Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome.
Mirko LuoniSerena GiannelliMarzia Tina IndrigoAntonio NiroLuca MassiminoAngelo IannielliLaura PasseriFabio RussoGiuseppe MorabitoPiera CalamitaSilvia GregoriBenjamin E DevermanVania BroccoliPublished in: eLife (2020)
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.
Keyphrases
- wild type
- binding protein
- gene expression
- dna methylation
- genome wide
- resting state
- white matter
- copy number
- spinal cord injury
- magnetic resonance imaging
- protein protein
- cerebral ischemia
- small molecule
- transcription factor
- computed tomography
- genome wide identification
- metabolic syndrome
- contrast enhanced
- newly diagnosed