Developing a Novel Therapeutic for Rett Syndrome
2018 Harrington Rare Disease Scholar
Rett syndrome is a rare chromosomal disorder that occurs almost exclusively in girls, usually recognized at 6 to 18 months, when symptoms arise that include motor abnormalities, severe seizures, absent speech, and autism. Individuals typically live wheelchair-bound for 40 years or more and require full-time care. There is no disease-specific treatment or cure.
Rett is caused by mutations on the X chromosome, specifically on the MECP2 gene that is crucial for neuronal development. Females have two X chromosomes, but only one is expressed in any cells, and the other is inactive.
In Rett girls, every affected cell harbors a normal but dormant copy of MECP2 on the inactive X chromosome. Dr. Lee's aim is to alleviate disease by reactivating that dormant chromosome to restore MECP2 protein to the brain.
"There's a central molecule, Xist RNA, that orchestrates the X chromosome shutdown," Dr. Lee says. "Then DNA methylation (a process that plays a crucial role in regulation of gene expression) cements that shutdown. After years of trial and error, I had an epiphany: because no single compound can reactivate the X chromosome sufficiently, why not combine two modalities in such a way that the whole is greater than the sum of the parts? So we used drugs to target both of them - lo and behold, we got reactivation."
Dr. Lee claims that this approach can potentially be applied to other diseases caused by mutations on the X chromosome.
“The Harrington Therapeutic Development team has made a huge difference to our drug discovery efforts, bringing logistical support not typically found in academia."