title: Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice.
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.
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Kamal K E
authors.initials: KK
authors.lastname: Gadalla
authors.forename: Mark E S
authors.initials: ME
authors.lastname: Bailey
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: Spike
authors.forename: Paul D
authors.initials: PD
authors.lastname: Ross
authors.forename: Kenton T
authors.initials: KT
authors.lastname: Woodard
authors.forename: Sahana Nagabhushan
authors.initials: SN
authors.lastname: Kalburgi
authors.forename: Lavanya
authors.initials: L
authors.lastname: Bachaboina
authors.forename: Jie V
authors.initials: JV
authors.lastname: Deng
authors.forename: Anne E
authors.initials: AE
authors.lastname: West
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Gray
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Cobb
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D015518:Rett Syndrome / Q000235:genetics / Q000628:therapy*; D015996:Survival Rate