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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.

SUBMITTER: Gadalla KK

PROVIDER: S-EPMC3536818 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Gadalla Kamal K E KK Bailey Mark E S ME Spike Rosemary C RC Ross Paul D PD Woodard Kenton T KT Kalburgi Sahana Nagabhushan SN Bachaboina Lavanya L Deng Jie V JV West Anne E AE Samulski R Jude RJ Gray Steven J SJ Cobb Stuart R SR

Molecular therapy : the journal of the American Society of Gene Therapy 20120925 1

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 wee ...[more]

PMID: 23011033

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Project description:BackgroundIt is well-established that organizational effects of sex steroids during early development are fundamental for sex-typical displays of, for example, mating and aggressive behaviors in rodents and other species. Male and female brains are known to differ with respect to neuronal morphology in particular regions of the brain, including the number and size of neurons, and the density and length of dendrites in nuclei of hypothalamus and amygdala. The aim of the present study was to use global proteomics to identify proteins differentially expressed in hypothalamus/amygdala during early development (postnatal day 8) of male, female and conditional androgen receptor knockout (ARNesDel) male mice, lacking androgen receptors specifically in the brain. Furthermore, verification of selected sexually dimorphic proteins was performed using targeted proteomics.ResultsOur proteomic approach, iTRAQ, allowed us to investigate expression differences in the 2998 most abundantly expressed proteins in our dissected tissues. Approximately 170 proteins differed between the sexes, and 38 proteins between ARNesDel and control males (p < 0.05). In line with previous explorative studies of sexually dimorphic gene expression we mainly detected subtle protein expression differences (fold changes <1.3). The protein MARCKS (myristoylated alanine rich C kinase substrate), having the largest fold change of the proteins selected from the iTRAQ analyses and of known importance for synaptic transmission and dendritic branching, was confirmed by targeted proteomics as differentially expressed between the sexes.ConclusionsOverall, our results provide solid evidence that a large number of proteins show sex differences in their brain expression and could potentially be involved in brain sexual differentiation. Furthermore, our finding of a sexually dimorphic expression of MARCKS in the brain during development warrants further investigation on the involvement in sexual differentiation of this protein.

Project description:BackgroundMECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder primarily affecting males which is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Core clinical features of MDS include choreiform movements, progressive spasticity, recurrent respiratory infections, developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism. Prior studies suggest that HPA axis activity may be altered in MDS and measures of HPA axis activity may offer insight into disease severity.MethodsTo ascertain whether cortisol profiles are a potential biomarker of clinical severity, diurnal profiles of cortisol and the cortisol awakening response were examined from saliva samples in 31 participants with MDS (ages 2-24 years), and 27 of these samples were usable. Documentation of a positive diagnostic test for MECP2 duplication was required for entry into the study. Samples were collected on each of two consecutive weekdays at four time points during the day: immediately after waking, 30 min after waking, between 3 and 4 PM, and in the evening before bedtime. Correlations with duplication size, clinical severity, sleep problems, and behavior were also examined.ResultsResults revealed that a majority of participants with MDS exhibit a declining cortisol awakening response (n = 17). A declining CAR was significantly associated with increased clinical severity scores (r = - .508; p = .03), larger duplication size, waking later, and an increased number of hospitalizations for infections.ConclusionsFuture mechanistic studies will have to determine whether the declining CAR in MDS is attributable to problems with "flip-flop switching" of regional brain activation (involving the suprachiasmatic nucleus and the hippocampus, and the HPA axis) that is responsible for the switch from reduced to increased adrenal sensitivity. Taken together, results suggest the possibility that cortisol profiles could potentially be a biomarker of clinical severity and utilized for the purposes of patient stratification for future clinical trials in MDS.

Dataset Information

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

Publications

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

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