Reversión de fenotipos en ratones

Prof. Huda Zoghbi et al (Baylor College of Medicine, Texas, USA) published an article in the journal *Nature* entitled ‘Reversible phenotype in mice using gene rescue or antisense oligonucleotides’. This article presents the results of using antisense oligonucleotides to correct MeCP2 levels and reverse behavioural, molecular and electrophysiological abnormalities 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)

SUMMARY OF THE PUBLICATION:

Variations in copy number have frequently been 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 characterised by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and premature death.

The wide range of deficits caused by the overexpression of the methyl-CpG-binding protein 2 (MeCP2) poses an enormous challenge to traditional therapeutic treatments based on biochemical pathways. Consequently, we are seeking strategies that target MeCP2 directly and have the potential to be translated into clinical therapy.

The first question we focused on was whether neurological dysfunction is reversible following the onset of symptoms. Reversal of phenotypes in symptomatic adult mice has been demonstrated in some models of monogenic loss of function in neurological disorders, including MeCP2 loss in Rett syndrome. This suggests that, at least in some cases, the neuroanatomy may remain sufficiently intact such that correcting the molecular dysfunction underlying these disorders can restore healthy physiology.

Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoring normal MeCP2 levels in adult mice with MECP2 duplication would reverse their phenotype.

By generating and characterising a model of conditional MeCP2 overexpression in mice, we demonstrated that MeCP2 correction largely reverses behavioural, molecular and electrophysiological deficits.

We also reduced MeCP2 levels using an antisense oligonucleotide strategy, which has greater translational potential.

Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridise with the messenger RNA transcribed from a target gene and silence it; this technique has been used successfully to correct defects in various mouse models.

We have found that treatment with antisense oligonucleotides induces extensive phenotypic rescue in symptomatic adult transgenic mice with MECP2 duplication (MECP2-TG) and corrects MeCP2 levels in lymphoblastoid cells from patients with MECP2 duplication in a dose-dependent manner.