Reversible symptoms in mice

Prof. Huda Zoghbi et al (Baylor College of Medicine, Texas, USA) have published an article in the journal Nature entitled "Reversible phenotype in mice using genetic rescue or antisense oligonucleotides". This article presents the results of using antisense oligonucleotides (ASOs) to correct MeCP2 levels and reverse behavioural, molecular and electrophysiological disorders in an animal model with a duplication of the MECP2 gene.

Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides, Huda Zoghbi et al, Nature 528, 123-126 (2015)

ARTICLE SUMMARY (Translated from English):

Copy number variation has frequently been associated with developmental delay, intellectual disability and the autistic spectrum. The MECP2 gene duplication syndrome is a genome rearrangement affecting mainly males and is characterised by an autistic spectrum, intellectual disability, motor dysfunction, anxiety, epileptic seizures, respiratory infections and early death.

The wide variety of deficits caused by overexpression of the MeCP2 protein represents a major challenge for traditional therapeutic approaches based on biochemical pathways. We have therefore investigated therapeutic strategies that directly target the MeCP2 protein and have the potential to be translated into clinical therapy.

The first question we addressed was whether neurological dysfunction is reversible after the onset of symptoms. The reversal of phenotypes in symptomatic adult mice has been demonstrated in some models of monogenic loss of neurological function, notably the loss of MeCP2 in Rett syndrome. This indicates that, at least in some cases, neuroanatomy may remain sufficiently intact for correction of the molecular dysfunction underlying these disorders to restore healthy physiology.

Given the absence of neurodegeneration in MECP2 duplication syndrome, we believe that restoring normal levels of MeCP2 in adult mice with MECP2 duplication should correct their phenotype.

By generating and characterising a mouse model overexpressing Mecp2, we show here that correction of MeCP2 levels largely reverses 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 used successfully to correct deficiencies in various mouse models.

We find that antisense oligonucleotides induce broad phenotype recovery in adult symptomatic transgenic mice with MECP2 duplication and correct MeCP2 levels, in a dose-dependent manner, in lymphoblastoid cells from patients with MECP2 duplication.