title: Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome.
abstract: De novo mutations in the X-linked gene encoding the transcription factor methyl-CpG binding protein 2 (MECP2) are the most frequent cause of the neurological disorder Rett syndrome (RTT). Hemizygous males usually die of neonatal encephalopathy. Heterozygous females survive into adulthood but exhibit severe symptoms including microcephaly, loss of purposeful hand motions and speech, and motor abnormalities, which appear after a period of apparently normal development. Most studies have focused on male mouse models because of the shorter latency to and severity in symptoms, yet how well these mice mimic the disease in affected females is not clear. Very few therapeutic treatments have been proposed for females, the more gender-appropriate model. Here, we show that self-complementary AAV9, bearing MeCP2 cDNA under control of a fragment of its own promoter (scAAV9/MeCP2), is capable of significantly stabilizing or reversing symptoms when administered systemically into female RTT mice. To our knowledge, this is the first potential gene therapy for females afflicted with RTT.
authors: Oregon Health and Science University, Portland, OR, USA.
authors: Saurabh K
authors: SK
authors: Garg
authors: Daniel T
authors: DT
authors: Lioy
authors: Hélène
authors: H
authors: Cheval
authors: James C
authors: JC
authors: McGann
authors: John M
authors: JM
authors: Bissonnette
authors: Matthew J
authors: MJ
authors: Murtha
authors: Kevin D
authors: KD
authors: Foust
authors: Brian K
authors: BK
authors: Kaspar
authors: Adrian
authors: A
authors: Bird
authors: Gail
authors: G
authors: Mandel
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D002452:Cell Count; D000229:Dependovirus / Q000502:physiology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010991:Plethysmography; D004856:Postural Balance / Q000235:genetics / Q000502:physiology; D021641:Recognition, Psychology / Q000502:physiology; D012119:Respiration; D015518:Rett Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D045442:Rotarod Performance Test
chemical_list: D005904:Glial Fibrillary Acidic Protein; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D010751:Phosphopyruvate Hydratase
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