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

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