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)
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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 > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience College of Medical Veterinary and Life Sciences > School of Life Sciences College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Molecular Therapy |
| Journal Abbr.: | Mol. Ther. |
| Publisher: | Nature Publishing Group |
| ISSN: | 1525-0016 |
| ISSN (Online): | 1525-0024 |
| Published Online: | 25 September 2012 |
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