Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligos

Copy number variations have been frequently associated with developmental delay, intellectual disability, and autism spectrum disorders(1). MECP2 duplication syndrome is one of the most common genomic rearrangements in males(2) and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections, and early death(3–5). 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, however, 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(6–8), including loss of MeCP2 in Rett syndrome(9), 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 hypothesized that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. Therefore, we first generated and characterized a conditional Mecp2-overexpressing mouse model and showed that correction of MeCP2 levels largely reversed the behavioral, molecular, and electrophysiological deficits. Next, we sought a translational strategy to reduce MeCP2 and turned to antisense oligonucleotides (ASOs). ASOs are small modified nucleic acids that can selectively hybridize with mRNA transcribed from a target gene and silence it(10,11), and have been successfully used to correct deficits in different mouse models(12–18). We found that ASO treatment induced 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.