Exosome Biomarkers of Epilepsy in Tuberous Sclerosis Complex Patients
Abstract
Scientific Objective and Rationale: Epilepsy occurs in approximately 90% of tuberous sclerosis complex (TSC) patients. Up to three-fourths of these patients will become drug resistant to anti-epileptic drugs (AED), and their seizures will not be effectively controlled. Ongoing seizures lead to debilitating effects, such as cognitive decline, behavioral disorders, and reduced quality of life. To prevent the onset of epilepsy and the subsequent neurological effects, there is great interest in using prophylactic (preventative) anti-epileptic drug treatment in TSC patient, where AEDs are prescribed prior to the beginning of observable seizures. However, this approach requires accurate testing methods that can identify TSC patients who would benefit from preventative treatment. Recent studies have investigated the use of serial electroencephalography (EEG) to monitor changes in electrical activity of the brain that may indicate the potential for seizures prior to the onset of epilepsy. Trials of this approach coupled with prophylactic AEDs have demonstrated the ability to delay epilepsy and improve neurocognitive outcomes. However, the use of serial EEG for this purpose has challenges, including imperfect ability to predict impending seizures, and difficulty for some patients to comply with a rigorous schedule of clinical visits. In the EPISTOP trial to prevent epilepsy in TSC, EEG was not able to predict the development of seizures in 23% of patients. The EPISTOP study reported that methods more sensitive than EEG to identify epileptogenesis are needed. Biological signals or molecules that can be used to indicate the presence or development of a disease are known as biomarkers. In this study, we propose to explore a new and innovative approach for biomarkers of epilepsy in TSC by detecting molecules in the blood that are secreted by the brain tubers that cause epilepsy. The goal of this research is to demonstrate proof of principle and establish the initial foundation for subsequent research that would use animal models and human studies to fully determine the pattern of these biomarkers in blood prior to the onset of seizures. Brain tubers cause epilepsy, and they secrete a unique signature of small vesicles called exosomes. Seizures in TSC arise from cortical tubers, but it is still unknown why some tubers are epileptogenic (cause seizures) while others are not. By analyzing brain tissue that was surgically removed for the treatment of drug-resistant epilepsy in TSC, our laboratory has extensively studied molecular differences between tubers that cause epilepsy and those that do not. We recently uncovered a distinct difference in small vesicles called exosomes that are secreted by cells. Importantly, exosomes are able to travel throughout the body via the bloodstream. We found that proteins in exosomes secreted by epileptogenic tubers are very different from those in exosomes secreted by non-epileptogenic tubers. Our recent publication indicates that these exosomes are likely involved in epileptogenesis and lowering of seizure thresholds. Additionally, we found that epileptogenic exosomes have a unique fingerprint of proteins that reflect the specific brain cell type that secreted the exosomes. If we are able to detect exosomes in the blood that are secreted from tubers as they become epileptogenic, then we will have the means to develop a new and powerful approach to predict the onset of epilepsy in TSC. We hypothesize that exosomes secreted from epileptogenic tubers will be detectable in blood. Using our preliminary analysis of exosomes in TSC brain tubers as a guide, we will first determine if exosomes secreted from epileptogenic tubers are detectable in the blood. During standard care of patients in our TSC Alliance designated clinic we will obtain a small amount of blood (1/10 of a teaspoon) while patients are having regularly scheduled blood draws for clinical analysis. From the blood, we will extract exosomes and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210798
Entities
People
- Alan A Dombkowski
Organizations
- United States Army
- Wayne State University