Shao et al. from Prof. Zoghbi’s group (Baylor College of Medicine, Texas, USA) published an article in Science Translational medicine entitled “Antisense oligonucleotide therapy in a humanized mouse model of MECP2 duplication syndrome”.
Each species has its own genes. The genes code for proteins that are unique to each species. It is possible that human and mouse proteins are slightly different. The model used in the presented work, called “humanized model”, allows to evaluate more the activity of antisense oligonucleotides (ASO) 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 antisense oligonucleotides in this mouse model of “humanized MECP2” gene duplication in which the mouse carries two human MECP2 alleles and no endogenous mouse alleles.
Administration effectively reduced MeCP2 expression throughout the brains of these mice, alleviated several behavioral deficits, and restored the expression of some 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)
PUBLICATION ABSTRACT
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.
