Reactivation of MECP2 and CDKL5 genes by functional deactivation of Xist RNA

Andrea Cerase, PhD | Queen Mary University of London

$351,022 AWARDED

Andrea Cerase is the newest member of the collaborative effort to wake up the healthy copy of MECP2 on the inactive X chromosome.

X inactivation is a process used to compensate for the double dose of X-chromosome genes that females (XX) receive compared to males (XY). Because only one X-chromosome is inactivated, every cell that has a mutated MECP2 gene on the active X, also contains a healthy copy of MECP2 on the inactive X-chromosome.

Inactivation of one female X chromosome is initiated by the non-coding RNA Xist. Dr. Cerase will evaluate the ability of a novel class of compounds to de-activate Xist and wake up the healthy gene on the inactive X chromosome. Some of the compounds that will be tested have been specifically designed to disrupt the binding of Xist to its silencing partners. Dr. Cerase has developed a highly quantitative and robust assay capable of detecting reactivation of MECP2 as well as a separate gene on the X chromosome, CDKL5. More than 20,000 novel peptidomimetic compounds will be screened to identify molecules that selectively reactivate MECP2 rather than the entire X chromosome. Importantly, these peptidomimetic compounds are designed to resist degradation in the bloodstream and to pass the blood-brain barrier, making them better candidates for future clinical development.

Once compounds have been identified that awaken MECP2, the work is not done. These compounds will then be characterized to determine the mechanism of MECP2 reactivation, if therapeutic levels of MeCP2 protein expression can be restored, if the compounds cross the blood-brain barrier, and if they are able to reverse Rett symptoms in animal models. This novel therapeutic discovery effort has the potential to significantly advance therapeutics not only for Rett Syndrome but also for many other disorders caused by mutations in genes on the X-chromosome.

Current Projects