Reversible symptoms in humanised mice

Shao et al. from Prof. Zoghbi's group (Baylor College of Medicine, Texas, USA) have published an article in the journal Science Translational Medicine entitled "Antisense oligonucleotide therapy in a humanised mouse model of MECP2 duplication syndrome".

Each species has its own genes. The genes code for proteins that are specific to each species. Human and murine proteins may be slightly different. The model used in the work presented, known as the "humanised model", makes it possible to assess the activity of antisense oligonucleotides (ASOs) specifically on the human protein produced by a mouse. It is therefore closer to the future use of ASO in humans.

This article presents the results obtained after intracerebroventricular injection of ASO in the mouse model of duplication of the "humanised MECP2" gene, in which the mouse carries two human MECP2 alleles and no endogenous mouse allele.

Administration effectively reduced MeCP2 expression throughout the brains of these mice, attenuated several behavioural deficits, and restored the expression of certain MeCP2-regulated genes in a dose-dependent manner and without any toxicity.

Antisense oligonucleotide therapy in a humanized mouse model of MECP2 duplication syndrome, Shao et al.Sci. Transl. Med. 13, 7785 (2021)

ARTICLE SUMMARY :

Many disorders leading to intellectual disability are due to copy number variations and, to date, no therapeutic options have been tested for this class of diseases. MECP2 duplication syndrome 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 have previously demonstrated that antisense oligonucleotide therapy (ASO) can reduce the amount of MECP2 protein in a mouse model with the duplication and reverse the symptoms characteristic of the syndrome.

However, this mouse model carried both a transgenic human allele and a mouse allele, the latter being protected from targeting by the human-specific ASO-MECP2.

MeCP2 is a protein with a high concentration. ASO must therefore be titrated so that the amount of MeCP2 is not too low, as this would cause Rett syndrome. Therefore, we generated a 'humanised MECP2' gene duplication model in which the mouse carries two human MECP2 alleles and no endogenous mouse allele. Intracerebroventricular injection of ASO-MECP2 effectively reduced MeCP2 expression throughout the brain of these mice. In addition, ASO-MECP2 attenuated several behavioural deficits and restored the expression of certain MeCP2-regulated genes in a dose-dependent manner and without any toxicity. Administration of ASO-MECP2 to the central nervous system is therefore well tolerated and beneficial in this mouse model and constitutes a transposable approach that could be considered for the treatment of MECP2 gene duplication syndromes.