The Role of Blood-Brain Barrier Dysfunction in Epilepsy in TSC
Abstract
This proposal addresses the FY20 TSCRP Focus Area of “Preventing epilepsy, improving treatment, and mitigating comorbidities associated with TSC-related seizures.” Epilepsy, a condition involving recurrent seizures, is a very common problem in tuberous sclerosis complex (TSC), occurring in up to 90% of all individuals with TSC. The seizures in TSC can be especially severe and impairing, causing a number of issues and complications for TSC patients, such as functional disability, loss of independence, social isolation, and increased risk of bodily injury and death. Furthermore, epilepsy in TSC usually does not respond well to currently available treatments, such as standard anti-seizure medications, as most TSC patients continue to have seizures despite multiple trials of different drugs and other treatments. Thus, the overall goal of this project is to develop novel, more effective therapies for epilepsy in TSC, which would significantly improve the quality of life of TSC patients, including potential preventative treatment. Most currently available medications for epilepsy work by acting on the primary cell type in the brain that causes seizures, called neurons. A novel therapeutic approach, which could improve efficacy and reduce side effects, is to target alternative non-neuronal mechanisms in the brain. In particular, blood vessels in the brain normally are relatively resistant to allowing substances in the blood to pass into the brain, a phenomenon referred to as the blood-brain barrier. Excessive leakiness of the blood-brain barrier has been implicated in contributing to some types of epilepsy, but this has never been examined in TSC. Previous studies in human tuber tissue and preliminary data for this grant suggest that blood vessels in TSC may be abnormal. In this grant proposal, we will use a mouse model of TSC to investigate whether the blood-brain barrier is abnormally leaky and contributes to epilepsy. Novel treatments targeting blood vessels and the blood-brain barrier will be tested for ability to prevent or attenuate seizures in the mouse model. The ultimate clinical application of this research is the identification of novel treatments for epilepsy in TSC patients, including preventative therapy. As some of the drugs in this proposal are already U.S. Food and Drug Administration-approved for other indications, this preclinical mouse model work could be translated relatively quickly into clinical trials in TSC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110286
Entities
People
- Michael Wong
Organizations
- United States Army
- Washington University in St. Louis