Rett syndrome is a non-inherited, rare neurological disorder that mostly affects girls and has no cure. This syndrome influences almost every part of the child’s life and is caused by mutations of the MeCP2 gene located on the X chromosome. Children affected by this syndrome show a variety of symptoms, including a worsening of the child’s ability to communicate, eat and move.
Like many diseases, much is unknown about Rett syndrome. Qiang Chang, an associate professor in the Departments of Medical Genetics and Neurology at UW-Madison and an investigator at the Waisman Center, is working to further understand Rett syndrome and its possible treatments.
According to Chang, the complexity of Rett syndrome is due to the great amount of involvement of the MeCP2 gene throughout the body. “You have a gene that is involved in many molecular functions and many cellular pathways. You’ve got it regulating many different processes,” Chang said. The variety of symptoms and pathways involved in the disease make it “particularly challenging to treat.”
Because the exact mechanisms that cause the myriad of symptoms of Rett syndrome symptoms are largely unknown, Chang predicts the best way to treat the disease would be through genome editing. With this method, the mutated MeCP2 gene of every cell in the body would be replaced with a corrected copy.
“The challenge in that approach is, how do you correct the mutation in every cell?” Chang said. In addition, for the cells that are no longer dividing, efficient genetic engineering tools are not available to precisely repair the mutation. If this were a viable option, Rett syndrome might be cured.
Chang believes that another approach would be to target and activate the chromosome containing the good copy of the gene in cells where the bad copy is active. Normally, females inherit two X chromosomes and during their development one of the copies is silenced at random. If the inactive X chromosome copy contains the mutated MeCP2 gene while the active copy is normal, the female would not be affected by Rett syndrome. If the inactive copy does not contain the mutated MeCP2 gene and the active copy does, the cell would express the effects of Rett syndrome. Deliberately targeting and activating the chromosome with the good copy must also afford a high level of specificity, or else it would pose a significant challenge.
“In a patient’s brain you have a mixture of good cells and bad cells, and if you want to turn on the good copies, you have to make sure you only turn on the good copies in the bad cells. You’d have to have some specificity in the reagent to target the good copies and not the bad copies.”
If a non-discriminative reagent or drug were used, regardless of whether the silenced copy of the gene in the cell were good or bad, it would be activated. In the end all the cells would have two active copies of the gene, which is problematic because instances occur in which the bad proteins from the bad copy interfere with the good proteins from the good copy.
Using mouse models and human stem cell models, Chang and his lab are furthering their biological understanding of the Rett syndrome symptoms and how they might be treated. In their current study, Chang was able to explore a pathway never studied in the context of Rett syndrome before by generating a human stem cell model that was accurate to the characteristics of the cells present in an individual with Rett syndrome.
The mutation of the MeCP2 gene causes a weakening of this specific pathway. Because this particular pathway has been studied in other contexts, drugs already exist to target it. “We were able to use one existing drug to enhance this pathway in the Rett syndrome cells so that it would reverse the deficit,” Chang said.
Both the Rett syndrome mice and Rett syndrome human cells were treated with the known drug and showed significant improvement. However, this drug is also known to have significant side effects, and therefore is not a viable treatment option for Rett syndrome patients.
Nonetheless, the human stem cell model developed by the Chang lab is now further validated. Understanding the accuracy of this model is important because it can be reliably used to test other drugs before they are tried in human patients.
“The laboratory studies basically just demonstrate, in general, that the principle is correct and then based on this principle we can go to the next step to find something that will be useful,” Chang said.
According to Chang, the future of Rett syndrome research has a clear direction. Many of the tools needed have already been developed. First, researchers can focus on targeting the root of the disease with genome editing. Second, researchers can look for specific ways to activate the normal copy of the X chromosome. Third, researchers can explore strategies that involve combining effective drugs for individual symptoms of the disease at once.
“I think we have those three general approaches to try to be closer to human use. [We’re] not just doing research to understand the basic biology anymore, but improving patient health.”
Hopefully in the near future, clinical trials will be performed using the approaches outlined by Chang. Though this rare disease does not yet have a cure, it is uplifting to know that new tools are being used to explore a variety of promising treatment options.