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

结节性硬化症（TSC）是一种罕见的由TSC1/2基因突变引起的遗传病。该突变导致哺乳动物靶雷帕霉素（mTOR）通路的过度活跃，可导致患者出现许多不同的症状。主要症状之一是癫痫，80%的患者发生癫痫，由大脑中形成的局灶性病变引起，称为“结节”。这些块茎导致TSC患者发展为严重的癫痫，对传统的抗癫痫药物没有反应。无法对TSC患者的癫痫进行药物治疗或控制是极其危险的，因为它可能导致不明原因猝死（SUDEP），这是TSC患者死亡的主要原因。依维莫司是一种mTOR抑制剂，目前被用作TSC患者的治疗选择。虽然依维莫司对许多其他TSC症状有效，但其减少癫痫发作的能力很低。这使得手术切除结节成为唯一的其他治疗方法，但这已被证明有不同的长期成功率。由于TSC患者癫痫治疗的临床需求未得到满足，因此TSC的药物研究是重中之重。赖氨酸代谢途径中的线粒体酶已被确定为TSC癫痫的潜在新药物靶点。该项目的目的是开发一种针对脑细胞中这种酶的新药，同时最大限度地减少这些药物的外周循环。因此，本项目旨在首先设计一种靶向线粒体酶的药物，然后利用分子和电化学参数对TSC诱导多能干细胞（iPSC）模型进行疗效评估。然后可以测量所设计药物的药代动力学特性，以确保通过血脑屏障的有效性。我们的目标是整合在阿斯顿开发的靶向线粒体的纳米颗粒递送系统来包装药物，以改善化合物直接递送到线粒体。此外，我们将与合作伙伴组织结节性硬化症协会（TSA）合作，让TSC患者社区直接参与我们的研究过程。

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.