Development of Neurophysiological Biomarkers in Rett Syndrome
Abstract
Rett syndrome (RTT) is a devastating neurological disorder that emerges in early childhood. RTT is made particularly tragic by the fact that children destined to be diagnosed with this disorder appear to be developing normally and gaining skills early in life. But then, between 18 and 30 months of age children experience loss of the ability to speak and use their hands and have problems walking or cannot walk at all. Unfortunately, these skills are not regained in any meaningful way, causing affected individuals to be severely impaired for the rest, leading to them requiring lifelong assistance in performing basic activities of daily living like feeding themselves and using the toilet. In addition to the loss of skills, people with RTT have many other problems, such as seizures, severe constipation, problems chewing and swallowing, poor growth, movement problems, changes in breathing patterns, as well as a number of problematic issues. Many of these problems are seen in other brain disorders that affect both children and adults. There are no approved therapies for RTT, and the approach to treatment is entirely based on giving medicines and therapies to treat the symptoms (like seizures), and the ability of these symptomatic treatments to make meaningful change is very limited. Nearly all people with RTT have a mutation in a gene called Methyl CpG binding protein 2 (MECP2), which reads signatures embedded in everyone’s DNA code that is important for how this code is used to control the activities of cells in the body. The MECP2 gene is on the X chromosome; for this reason, the most affected individuals are girls and women. Animal models of RTT have been created, and they show many of the same problems as those observed in people with RTT. Excitingly, the problems seen in these RTT animal models can be reversed, even after the problems are present, by turning the gene back on. This gives great hope that treatments can be developed for people that will change the course of the disease, or even reverse the problems seen in people with RTT. While work is underway to create new therapies for RTT, there are challenges in the ways available to do clinical trials of these therapies in a rare disease such as RTT as there are only a limited number of people who can participate in the trials. A missing element is that lack of biomarkers in RTT. A biomarker is something that can be measured and can tell or predict if someone has a disease, how well the body is functioning, or if there is a response to a treatment. For a rare disease like RTT, having a biomarker that shows response to treatment before clinical improvement could help make clinical trials faster and need less participants. An additional benefit would be a biomarker that can be seen in both people with RTT and in animal models of RTT, as this could be used in studies that evaluate new treatments in animal models, and then help guide human clinical trials. We found changes in brainwave activity and response to stimulus (measured with non-invasive EEG electroencephalogram) in people with RTT that are also seen in animal models. These EEG changes correlate with severity in people and animals with RTT, which makes them promising as biomarkers of response to treatment. To see if that is the case, in this proposal we will see if these EEG features improve when we turn the MECP2 gene on in a mouse model of RTT, and if they improve when we treat RTT mice with ketamine, which has been shown to improve the problems seen in these mice. Successful completion of this project will show if EEG can be used as a treatment responsive biomarker in RTT. Because these EEG features can be measured in animal models and people, this would help improve how therapies are testing in animal models and then in human clinical trials. This proposal addresses the Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Topic Area of Rett Syndrome (within the Neuroscience Portf
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310004
Entities
People
- Jeffrey Neul
Organizations
- United States Army
- Vanderbilt University