A mixed modality approach towards Xi reactivation for Rett syndrome and other X-linked disorders

The X-chromosome harbors hundreds of disease genes whose associated diseases predominantly affect males. However, a subset, including neurodevelopmental disorders, Rett syndrome (RTT), fragile X syndrome, and CDKL5 syndrome, also affects females. These disorders lack disease-specific treatment. Beca...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2018-01, Vol.115 (4), p.E668-E675
Main Authors: Carrette, Lieselot L. G., Wang, Chen-Yu, Wei, Chunyao, Press, William, Ma, Weiyuan, Kelleher, Raymond J., Lee, Jeannie T.
Format: Article
Language:English
Subjects:
5-aza-2'-deoxycytidine
Activation
Antisense oligonucleotides
Biocompatibility
Biological Sciences
Brain
Cell culture
Chromosomes
CpG islands
Deactivation
Deoxyribonucleic acid
Disorders
DNA
DNA methylation
Females
Fragile X syndrome
Genes
Inactivation
Intellectual disabilities
Males
MeCP2 protein
Medical treatment
Methyl-CpG binding protein
Molecules
Neurodevelopmental disorders
PNAS Plus
Restoration
Rett syndrome
Ribonucleic acid
RNA
Toxicity
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Summary:The X-chromosome harbors hundreds of disease genes whose associated diseases predominantly affect males. However, a subset, including neurodevelopmental disorders, Rett syndrome (RTT), fragile X syndrome, and CDKL5 syndrome, also affects females. These disorders lack disease-specific treatment. Because female cells carry two X chromosomes, an emerging treatment strategy has been to reawaken the healthy allele on the inactive X (Xi). Here, we focus on methyl-CpG binding protein 2 (MECP2) restoration for RTT and combinatorially target factors in the interactome of Xist, the noncoding RNA responsible for X inactivation. We identify a mixed modality approach combining an Xist antisense oligonucleotide and a small-molecule inhibitor of DNA methylation, which, together, achieve 30,000-fold MECP2 up-regulation from the Xi in cultured cells. Combining a brain-specific genetic Xist ablation with short-term 5-aza-2′-deoxycytidine (Aza) treatment models the synergy in vivo without evident toxicity. The Xi is selectively reactivated. These experiments provide proof of concept for a mixed modality approach for treating X-linked disorders in females.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1715124115