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

ABSTRACT: 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.

SUBMITTER: Carrette LLG

PROVIDER: S-EPMC5789928 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Carrette Lieselot L G LLG Wang Chen-Yu CY Wei Chunyao C Press William W Ma Weiyuan W Kelleher Raymond J RJ Lee Jeannie T JT

Proceedings of the National Academy of Sciences of the United States of America 20171227 4

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) restorat ...[more]

PMID: 29282321

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Project description:Epilepsy is common in Rett syndrome, an X-linked dominant disorder caused by mutations in the MECP2 gene, and in Rett-related disorders, such as MECP2 duplication. However, neither the longitudinal course of epilepsy nor the patterns of seizure onset and remission have been described in Rett syndrome and related conditions. The present study summarizes the findings of the Rett syndrome Natural History study. Participants with clinical Rett syndrome and those with MECP2 mutations without the clinical syndrome were recruited through the Rett Natural History study from 2006 to 2015. Clinical details were collected, and cumulative lifetime prevalence of epilepsy was determined using the Kaplan-Meier estimator. Risk factors for epilepsy were assessed using Cox proportional hazards models. Of 1205 participants enrolled in the study, 922 had classic Rett syndrome, and 778 of these were followed longitudinally for 3939 person-years. The diagnosis of atypical Rett syndrome with a severe clinical phenotype was associated with higher prevalence of epilepsy than those with classic Rett syndrome. While point prevalence of active seizures ranged from 30% to 44%, the estimated cumulative lifetime prevalence of epilepsy using Kaplan-Meier approached 90%. Specific MECP2 mutations were not significantly associated with either seizure prevalence or seizure severity. In contrast, many clinical features were associated with seizure prevalence; frequency of hospitalizations, inability to walk, bradykinesia, scoliosis, gastrostomy feeding, age of seizure onset, and late age of diagnosis were independently associated with higher odds of an individual having epilepsy. Aggressive behaviour was associated with lower odds. Three distinct patterns of seizure prevalence emerged in classic Rett syndrome, including those who did not have seizures throughout the study, those who had frequent relapse and remission, and those who had relentless seizures. Although 248 of those with classic Rett syndrome and a history of seizures were in terminal remission at last contact, only 74 (12% of those with a history of epilepsy) were seizure free and off anti-seizure medication. When studied longitudinally, point prevalence of active seizures is relatively low in Rett syndrome, although lifetime risk of epilepsy is higher than previously reported. While daily seizures are uncommon in Rett syndrome, prolonged remission is less common than in other causes of childhood onset epilepsy. Complete remission off anti-seizure medications is possible, but future efforts should be directed at determining what factors predict when withdrawal of medications in those who are seizure free is propitious.

Dataset Information

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

Publications

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

Similar Datasets

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