Reawakening inactivated X chromosomes to treat Rett syndrome

Reawakening inactivated X chromosomes to treat Rett syndrome

Females inherit an X chromosome from each parent, one of which is inactivated during embryonic development. As such, female somatic cells express either the maternal or paternal X chromosome in roughly equal numbers, a critical distinction in how disease-related mutations on the X chromosome affect men and women.

Researchers exploit the distinction to devise a mixed-mode treatment strategy for Rett syndrome, a neurodevelopmental disorder caused by a mutation in methyl-CpG binding protein 2 (MECP2) that largely afflicts young girls, causing severe seizures, motor abnormalities, speech deficits, and autism.

The authors’ therapeutic strategy reawakens the inactivated but healthy X allele with a two-pronged approach: an antisense oligonucleotide to target the noncoding RNA responsible for X-inactivation, or Xist, and a small-molecule inhibitor of DNA methylation. Acting synergistically, the two approaches upregulate MECP2 from cultured inactivated X chromosomes approximately 30,000-fold.

Furthermore, an in vivo model reveals that X chromosome reactivation occurs in the brains of mice with no apparent toxicity.

According to the authors, the approach can be applied to similar neurodevelopmental disorders, such as fragile X syndrome and CDKL5 syndrome.