Reversal of MECP2 duplication syndrome using genetic rescue and antisense oligonucleotides [ASO time point 1]

MECP2 duplication syndrome, a childhood neurological disorder characterized by autism, intellectual disability, motor dysfunction, anxiety and epilepsy, is caused by a duplication on chromosome Xq28 spanning the MECP2 gene that results in doubling of MeCP2 levels. MECP2 overexpression in mice causes neurobehavioral and electroencephalographic defects similar to those of human patients, but the gross anatomy of the brain remains unaffected. We hypothesized that MECP2 duplication syndrome would be reversible and tested two methods to restore MeCP2 levels to normal: conditional genetic recombination and antisense oligonucleotide therapy. Both approaches rescued molecular, physiological and behavioral features of adult symptomatic mice. Antisense therapy also restored normal MeCP2 levels in lymphoblastoid cells from MECP2 duplication patients, in a dose-dependent manner. Our data indicate that antisense oligonucleotides could provide a viable therapeutic approach for human MECP2 duplication syndrome as well as other disorders involving copy number gains. Overall design: Hippocampal mRNA profiles of WT, MECP2-TG and MECP2-TG ASO-treated treated mice 4weeks after the initiation of the treatment, were generated by deep sequencing, in triplicate, using Illumina TruSeq.

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Sztainberg Y, Chen HM, Swann JW, Hao S, Tang B, Wu Z, Tang J, Wan YW, Liu Z, Rigo F, Zoghbi HY