Engineering a novel mitochondrial-targeting drug for epilepsy in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a rare genetic disease caused by mutations in the TSC1/2 genes. The mutation results in hyperactivity of the mammalian target rapamycin (mTOR) pathway which can cause many different symptoms in patients. One of main symptoms is epilepsy which occurs in 80% of patients and is caused by focal lesions forming in the brain called 'tubers'. The tubers result in TSC patients developing severe epilepsy that does not respond to conventional antiepileptic drug. Not being able to medicate or control the epilepsy in TSC patients is extremely dangerous as it can lead to sudden unexplained death (SUDEP), which is a major cause of death for TSC patients.
Everolimus is a mTOR inhibitor and is currently used as a treatment option for TSC patients. Although everolimus is effective for many other symptoms of TSC, its ability to reduce seizures is low. This leaves surgical removal of the tubers being the only other treatment but this has been shown to have varying long-term success rates. Due to this unmet clinical need for epilepsy treatment in TSC patients, medicinal research is on high priority for TSC. A mitochondrial enzyme in the lysine metabolic pathway has been identified as potential new drug target for epilepsy in TSC. The aim of this project is to develop a new drug that targets this enzyme in the brain cells, while minimising peripheral circulation of these drugs.
Therefore, the project aims to firstly design a drug to target the mitochondrial enzyme and then assess the drug's efficacy using molecular and electrochemical parameters on induced pluripotent stem cell (iPSC) model of TSC. The pharmacokinetic properties of the designed drug can then be measured to ensure availability across the blood-brain barrier. We aim to integrate mitochondrial-targeting nanoparticle delivery system developed here at Aston to package the drug to improve delivery of the compound directly to the mitochondria. In addition, we will work with partner organization, Tuberous Sclerosis Association (TSA), to involve and engage the TSC patient community directly throughout our research process.