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

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. duplication syndrome (MDS) is one of the most common genomic rearrangements in males and results from duplications spanning the methyl-CpG binding protein 2 () 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 -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 " humanized" MDS model that carries two human alleles and no mouse endogenous allele. Intracerebroventricular injection of the -ASO efficiently down-regulated MeCP2 expression throughout the brain in these mice. Moreover, -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 -ASO is therefore well tolerated and beneficial in this mouse model and provides a translatable approach that could be feasible for treating MDS.