Details

Autor(en) / Beteiligte

• Carrette, Lieselot L. G.
• Wang, Chen-Yu
• Wei, Chunyao
• Press, William
• Ma, Weiyuan
• Kelleher, Raymond J.
• Lee, Jeannie T.

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2018-01, Vol.115 (4), p.E668-E675

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2018

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.