Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice

Gadalla, K.K.E. et al. (2013) Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. Molecular Therapy, 21(1), pp. 18-30. (doi:10.1038/mt.2012.200) (PMID:23011033) (PMCID:PMC3536818)

Full text not currently available from Enlighten.

Abstract

Typical Rett syndrome (RTT) is a pediatric disorder caused by loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. The demonstrated reversibility of RTT-like phenotypes in mice suggests that MECP2 gene replacement is a potential therapeutic option in patients. We report improvements in survival and phenotypic severity in Mecp2-null male mice after neonatal intracranial delivery of a single-stranded (ss) AAV9/chicken β-actin (CBA)-MECP2 vector. Median survival was 16.6 weeks for MECP2-treated versus 9.3 weeks for green fluorescent protein (GFP)-treated mice. ssAAV9/CBA-MECP2-treated mice also showed significant improvement in the phenotype severity score, in locomotor function, and in exploratory activity, as well as a normalization of neuronal nuclear volume in transduced cells. Wild-type (WT) mice receiving neonatal injections of the same ssAAV9/CBA-MECP2 vector did not show any significant deficits, suggesting a tolerance for modest MeCP2 overexpression. To test a MECP2 gene replacement approach in a manner more relevant for human translation, a self-complementary (sc) adeno-associated virus (AAV) vector designed to drive MeCP2 expression from a fragment of the Mecp2 promoter was injected intravenously (IV) into juvenile (4-5 weeks old) Mecp2-null mice. While the brain transduction efficiency in juvenile mice was low (~2-4% of neurons), modest improvements in survival were still observed. These results support the concept of MECP2 gene therapy for RTT. Molecular Therapy (2012); doi:10.1038/mt.2012.200.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cobb, Dr Stuart and Spike, Dr Rosemary and Bailey, Dr Mark
Authors: Gadalla, K.K.E., Bailey, M.E.S., Spike, R.C., Ross, P., Woodard, K.T., Kalburgi, S.N., Bachaboina, L., Deng, J.V., West, A.E., Samulski, R.J., Gray, S.J., and Cobb, S.R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Molecular Therapy
Journal Abbr.:Mol. Ther.
Publisher:Nature Publishing Group
ISSN:1525-0016
ISSN (Online):1525-0024
Published Online:25 September 2012

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
480301Reversibility and mapping of Rett Syndrome-like phenotypes in the mouse brainStuart CobbMedical Research Council (MRC)G0800401/86343RI NEUROSCIENCE & PSYCHOLOGY