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

eLife

Piera Calamita¹  Laura Passeri²  Fabio Russo²  Silvia Gregori²  Benjamin Deverman³  Giuseppe Morabito⁴  Luca Massimino⁴  Serena Giannelli⁴  Marzia Tina Indrigo⁴  Mirko Luoni⁵  Antonio Niro⁵  Angelo Iannielli⁵  Vania Broccoli⁵ 

[1] National Institute of Molecular Genetics (INGM), Milan, Italy;San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), San Raffaele Scientific Institute IRCCS, Via Olgettina, Milan, Italy;Stanley Center for Psychiatric Research at Broad Institute, Cambridge, United States;Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy;Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy;CNR Institute of Neuroscience, Milan, Italy;

关键词: intellectual disabilities;    AAV;    gene therapy;    neuronal disease;    Mouse;   

DOI  :  10.7554/eLife.52629

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY