Research ArticleDrug Development

Antisense oligonucleotide therapy in a humanized mouse model of MECP2 duplication syndrome

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Science Translational Medicine  03 Mar 2021:
Vol. 13, Issue 583, eaaz7785
DOI: 10.1126/scitranslmed.aaz7785

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A SOlution for MDS in humanized mice

MECP2 duplication syndrome (MDS) is a genetic disorder characterized by severe intellectual disability, motor dysfunctions, and seizures. MECP2-specific antisense oligonucleotides (MECP2-ASOs) have shown promising results in mice, normalizing MeCP2 protein concentration in the brain. In anticipation of clinical trials, Shao et al. now generated a humanized mouse model of MDS that carries two human MECP2 alleles and no mouse endogenous alleles. The authors characterized the effects of MECP2-ASO intracerebral administration and showed a dose-dependent reduction in MeCP2 expression in the brain. The treatment reversed behavioral and molecular abnormalities in this model, suggesting that the approach might be therapeutic in patients with MDS.


Many intellectual disability disorders are due to copy number variations, and, to date, there have been no treatment options tested for this class of diseases. MECP2 duplication syndrome (MDS) is one of the most common genomic rearrangements in males and results from duplications spanning the methyl-CpG binding protein 2 (MECP2) gene locus. We previously showed that antisense oligonucleotide (ASO) therapy can reduce MeCP2 protein amount in an MDS mouse model and reverse its disease features. This MDS mouse model, however, carried one transgenic human allele and one mouse allele, with the latter being protected from human-specific MECP2-ASO targeting. Because MeCP2 is a dosage-sensitive protein, the ASO must be titrated such that the amount of MeCP2 is not reduced too far, which would cause Rett syndrome. Therefore, we generated an “MECP2 humanized” MDS model that carries two human MECP2 alleles and no mouse endogenous allele. Intracerebroventricular injection of the MECP2-ASO efficiently down-regulated MeCP2 expression throughout the brain in these mice. Moreover, MECP2-ASO mitigated several behavioral deficits and restored expression of selected MeCP2-regulated genes in a dose-dependent manner without any toxicity. Central nervous system administration of MECP2-ASO is therefore well tolerated and beneficial in this mouse model and provides a translatable approach that could be feasible for treating MDS.

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