Tuberous sclerosis complex (TSC) is a rare genetic disease caused by mutations in the TSC1/2 genes. Patients of TSC present with many symptoms; including focal lesions in the brain called ‘tubers’. These tubers are highly epileptogenic; leading to 80% of TSC patients developing severe epilepsy that does not respond to conventional antiepileptic drug. Uncontrolled epilepsy in TSC is incredibly dangerous as it can lead to sudden unexplained death (SUDEP), a major cause of death for TSC patients.
Current treatment option for TSC patients include mTOR inhibitors like everolimus. While everolimus is effective for many other symptoms of TSC, its efficacy for seizure reduction is low. The only remaining treatment option is surgical removal of the tubers; which can be effective but long-term success rate is variable. Thus, epilepsy in TSC remains an unmet clinical need and is a pressing priority for drug development studies in TSC.
We have identified a mitochondrial enzyme in lysine metabolism as potential new drug target for epilepsy in TSC. We intend to develop a new drug that targets this enzyme in the brain cells; while minimizing peripheral circulation of these drugs. Thus, this project aims to:
1. Design a drug to target this mitochondrial enzyme. This will involve medicinal chemistry, lipid biosynthesis, and packaging of the drug into bespoke mitochondrial-targeting nanoparticles. We will also measure uptake of these lipid nanoparticles using advanced spectroscopy detection.
2. Testing the efficacy of this compound on induced pluripotent stem cell (iPSC) model of TSC. We will test the drug effect on: (1) electrophysiological properties of the neuron and (2) electrochemistry readout of mitochondrial reactive oxygen species formation.
3. Measuring the pharmacokinetic properties of designed compound to ensure availability across the blood-brain barrier
In addition to the research aims above, the student will work with our partner organizations; the Tuberous Sclerosis Association (TSA) and Birmingham Children’s Hospital; to gain opportunity to work and interact with the TSC patients directly.
This project involves multidisciplinary collaboration and offers outstanding research training opportunity; paired with patient-public involvement (PPI) in research.
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