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

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.

• Authors: Yingyao Shao, Yehezkel Sztainberg, Qi Wang, Sameer S Bajikar, Alexander J Trostle, Ying-Wooi Wan, Paymaan Jafar-Nejad, Frank Rigo, Zhandong Liu, Jianrong Tang, Huda Y Zoghbi
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 583 (03 03 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 33658357 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Mecp2 protein, mouse
• Methyl-CpG-Binding Protein 2
• Oligonucleotides, Antisense

Topics

• Animals
• DNA Copy Number Variations
• Mental Retardation, X-Linked (therapy)
• Methyl-CpG-Binding Protein 2 (genetics)
• Mice
• Oligonucleotides, Antisense (therapeutic use)