Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders1. MECP2 duplication syndrome is one of the most common genomic rearrangements in males2 and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death3,4,5. 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 disorders6,7,8, including loss of MeCP2 in Rett syndrome9, 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 it10,11, and have been successfully used to correct deficits in different mouse models12,13,14,15,16,17,18. We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult symptomatic transgenic MECP2 duplication mice (MECP2-TG)19,20, and corrected MECP2 levels in lymphoblastoid cells from MECP2 duplication patients in a dose-dependent manner.
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Gene Expression Omnibus
RNA-seq data have been deposited in the Gene Expression Omnibus under accession number GSE71235.
We thank R. Jaenisch for the Mecp2tm1Jae mice, S. Chun for ASOs tolerability studies in wild-type mice, L. Lombardi, M. Rousseaux, C. Alcott and V. Brandt for critical input, and C. Spencer for behavioural assays training. We are indebted to the patients and families who participated in this study. This project was funded by the National Institutes of Health (5R01NS057819 and 5P30HD024064 to H.Y.Z.), the Rett Syndrome Research Trust (401 Project), the Carl. C. Anderson, Sr and Marie Jo Anderson Charitable Foundation, the Howard Hughes Medical Institute (H.Y.Z.), NSF DMS-1263932 (Z.L.), and the Baylor Intellectual Disabilities Research Center (1U54HD083092) neurovisualization, neuroconnectivity and neurobehavioral cores.
Extended data figures
Extended data tables
This video shows a spontaneous seizure from a 30-week old male MECP2 duplication transgenic mouse during EEG recording.