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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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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cited_by cdi_FETCH-LOGICAL-c509t-130cfaf87516e74123801ed30bd22c0de3789ac098cc5a978aeb51a9bb46e9593
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container_title Proceedings of the National Academy of Sciences - PNAS
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creator Carrette, Lieselot L. G.
Wang, Chen-Yu
Wei, Chunyao
Press, William
Ma, Weiyuan
Kelleher, Raymond J.
Lee, Jeannie T.
description 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.
doi_str_mv 10.1073/pnas.1715124115
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G. ; Wang, Chen-Yu ; Wei, Chunyao ; Press, William ; Ma, Weiyuan ; Kelleher, Raymond J. ; Lee, Jeannie T.</creator><creatorcontrib>Carrette, Lieselot L. G. ; Wang, Chen-Yu ; Wei, Chunyao ; Press, William ; Ma, Weiyuan ; Kelleher, Raymond J. ; Lee, Jeannie T.</creatorcontrib><description>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. 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source JSTOR Archival Journals and Primary Sources Collection; PubMed Central
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
title A mixed modality approach towards Xi reactivation for Rett syndrome and other X-linked disorders
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