Developing a Novel Therapy for Neurological Symptoms of Tuberous Sclerosis Complex
Abstract
Tuberous sclerosis complex (TSC) is a genetic disease that affects many vital organs, including the brain. Neurological symptoms of TSC include seizures, autistic behavior, and intellectual disability. While the number and location of cortical tubers is accountable for some neurological symptoms, there is also a broad spectrum of the symptoms among patients with the same tuber burdens. This is because microscopic abnormalities of neuronal connections also play a significant role in neurological symptoms of TSC. Although rapamycin and its derivatives are promising therapies, they may not selectively and efficiently intervene in all synaptic dysfunctions. We found that knockout mice without TSC1 function have higher amounts of the particular neurotransmitter receptor. Remarkably, an inhibitor of this new target corrects excessive dendritic activities in Tsc1 knockout neurons. This compound also improved the premature death of the Tsc1 knockout mouse model. In this proposal, we will further characterize the therapeutic effect of this compound using anatomical, functional, and behavioral analyses, and determine if it improve seizures and features of TSC-Associated Neuropsychiatric Disorders (TAND) such as autistic behaviors and sleep disturbance. We will also examine several other drugs that inhibit the same receptor and select the best candidate to further test in mutant mice. Many of these candidate drugs have already been used in patients with other diseases. Positive outcomes of this preclinical study will offer a new therapeutic option that complements mTOR inhibitor treatment and, therefore, directly and profoundly impact the care of patients who have refractory epilepsy and TAND.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110356
Entities
People
- Akira Yoshii
Organizations
- United States Army
- University of Illinois at Chicago