Whole brain delivery of an instability-prone <i>Mecp2</i> transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome.

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 <i>MECP2</i> 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 <i>Mecp2</i> (i<i>Mecp2</i>) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral <i>Mecp2</i> transgene, limits supraphysiological Mecp2 protein levels. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic <i>Mecp2</i> mutant mice significantly improved locomotor activity, lifespan and gene expression normalization. Remarkably, PHP.eB-iMecp2 administration was well tolerated in female <i>Mecp2</i> mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male <i>Mecp2</i> mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of i<i>Mecp2</i> provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain.