Whole brain delivery of an instability-pronetransgene 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 sinceis 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 viraltransgene, limits supraphysiological Mecp2 protein levels. Intravenous injections of the PHP.eB-iMecp2 virus in symptomaticmutant mice significantly improved locomotor activity, lifespan and gene expression normalization. Remarkably, PHP.eB-iMecp2 administration was well tolerated in femalemutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated malemutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of iprovided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain.