Treatment of Epilepsy in Tuberous Sclerosis Complex by Interneuron Progenitor Transplantation
Abstract
This project will address the Focus Area: Preventing epilepsy, improving treatment, and mitigating neurodevelopmental outcomes associated with tuberous sclerosis complex (TSC)-related seizures, by providing key data on the efficacy of inhibitory cell transplantation-based therapy for intractable focal epilepsy associated with TSC. Since neural excitatory-inhibitory imbalance also underlies TSC-Associated Neuropsychiatric Disorders (TAND), this project may also address the Focus Area: Understanding and treating the features of TAND and reducing their impact. More than 80% of patients with TSC exhibit epilepsy. For many of these patients, the only therapeutic option is surgical resection, but less than 50% are able to achieve proper postsurgery seizure management. Recent advances in TSC research have led to the promise of new drugs, but there are significant concerns and limitations in their clinical use, particularly in young patients. The goal of our research is to develop an effective alternative approach that is minimally invasive and offers better seizure control and postoperative morbidity. Toward this goal, in the proposed project, we will test out hypothesis that local transplantation of inhibitory neural cells targeted to the site of epileptogenesis will ameliorate seizure activities in TSC, using a unique mouse model that recapitulates the focal epilepsy in TSC. Our proposed study is based on recent successes of interneuron progenitor transplantation by other groups to reduce epileptic activity in different types of epilepsy (i.e., temporal lobe epilepsy and generalized epilepsy) in animal models. A clinical trial has been started for the treatment of drug-resistant unilateral mesial temporal lobe epilepsy. We will test whether a similar approach can reduce highly refractory epilepsy with more focal epileptogenic sites, as seen in TSC. Considering the highly focal nature of epilepsy in TSC, we will also test the potential benefit of targeted transplantation using a micron-scale device, which our laboratory has recently developed, expecting that it will concentrate the inhibitory function of transplanted cells at the focal domain. If these results prove that epilepsy is suppressed in mice with TSC, they are expected to eventually lead to clinical trials as a treatment for TSC patients with intractable focal epilepsy for which surgical resection is the only treatment option. The benefits of this approach would include potential permanent cure of epilepsy, improvement of otherwise intractable epilepsy, and provide better postsurgical control than surgical resection. Potential risks would include the possibility of tumorigenicity, host inflammatory response, and sensorimotor impairments. To avoid or reduce such risks, approaches such as the induced cell death method, which destroys the transplanted cells, have already been considered. Given the successful initiation of a clinical trial for drug-resistant unilateral mesial temporal lobe epilepsy with a similar interneuron progenitor cell transplantation approach, we anticipate that the proposed study, if successful, will lead to clinical trials in 10 years. The results of this exploratory study are expected to provide essential data for further research on the application of cell transplantation-based therapies for intractable focal epilepsy associated with TSC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310208
Entities
People
- Masaaki Torii
Organizations
- United States Army