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

Genetic correction of MeCP2 levels largely reversed the behavioural, molecular and physiological deficits associated with MECP2 duplication syndrome in a transgenic mouse model; similarly, reduction of MeCP2 levels using an antisense oligonucleotide strategy resulted in phenotypic rescue in adult transgenic mice, and dose-dependently corrected MeCP2 levels in cells from patients with MECP2 duplication. Potential reversal of a developmental disorder MECP2 duplication syndrome is a childhood disorder caused by duplication of the MECP2 gene and, consequently, increased MECP2 protein levels. Huda Zoghbi and colleagues report that genetic correction of MECP2 levels largely reverses the behavioural, molecular and physiological deficits in a transgenic mouse model. Reducing MECP2 levels using an antisense oligonucleotide (ASO) strategy—which has greater potential for therapeutic application—similarly resulted in phenotypic rescue in adult transgenic mice and dose-dependently corrected MECP2 levels in cells from patients with MECP2 duplication. These findings suggest that a disorder caused by copy number variation can be reversed after symptoms have emerged. 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 , 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 disorders 6 , 7 , 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 propose that restoration of normal MeCP2 levels in MECP2 duplicat