title: Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides.
abstract: Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders. MECP2 duplication syndrome is one of the most common genomic rearrangements in males and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death. The broad range of deficits caused by methyl-CpG-binding protein 2 (MeCP2) overexpression poses a daunting challenge to traditional biochemical-pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MeCP2 and are amenable to translation into clinical therapy. The first question that we addressed was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders, including loss of MeCP2 in Rett syndrome, indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional Mecp2-overexpressing mouse model, here we show that correction of MeCP2 levels largely reverses the behavioural, molecular and electrophysiological deficits. We also reduced MeCP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with messenger RNA transcribed from a target gene and silence it, and have been successfully used to correct deficits in different mouse models. We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult symptomatic transgenic MECP2 duplication mice (MECP2-TG), and corrected MECP2 levels in lymphoblastoid cells from MECP2 duplication patients in a dose-dependent manner.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Yehezkel
authors.initials: Y
authors.lastname: Sztainberg
authors.affiliation: The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Hong-mei
authors.initials: HM
authors.lastname: Chen
authors.affiliation: The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Swann
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Hao
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Tang
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Tang
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Ying-Wooi
authors.initials: YW
authors.lastname: Wan
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Zhandong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, California 92010, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D000818:Animals; D001287:Attachment Sites, Microbiological / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004569:Electroencephalography; D018628:Gene Dosage / Q000235:genetics*; D020440:Gene Duplication / Q000235:genetics; D055785:Gene Knockdown Techniques; D020131:Genes, Duplicate / Q000235:genetics*; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D010641:Phenotype
chemical_list: C497392:MECP2 protein, human; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D016376:Oligonucleotides, Antisense; C045073:Cre recombinase; D019426:Integrases