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

结节性硬化症(TSC)是一种罕见的遗传病，由TSC1/2基因突变引起。这种突变会导致哺乳动物靶向雷帕霉素(MTOR)途径的过度活跃，这可能会导致患者出现许多不同的症状。主要症状之一是癫痫，它发生在80%的患者中，由大脑中形成的称为结节的局灶性病变引起。这些块茎导致TSC患者患上对传统抗癫痫药物无效的严重癫痫。无法对TSC患者的癫痫进行药物治疗或控制是极其危险的，因为它可能导致原因不明的猝死(SUDEP)，这是TSC患者的主要死亡原因。依维莫司是一种mTOR抑制剂，目前被用作TSC患者的治疗选择。尽管依维莫司对TSC的许多其他症状有效，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，但这一方法被证明具有不同的长期成功率。由于TSC患者对癫痫治疗的临床需求尚未得到满足，TSC的药物研究是高度优先的。赖氨酸代谢途径中的一种线粒体酶已被确定为TSC治疗癫痫的潜在新药靶点。该项目的目的是开发一种针对脑细胞中这种酶的新药，同时将这些药物的外周循环降至最低。因此，本项目的目标是首先设计一种针对线粒体酶的药物，然后利用分子和电化学参数评估该药物在TSC诱导多能干细胞(IPSC)模型上的疗效。然后可以测量设计药物的药代动力学特性，以确保跨血脑屏障的有效性。我们的目标是集成在阿斯顿开发的线粒体靶向纳米颗粒递送系统，以包装药物，以改善化合物直接向线粒体的递送。此外，我们将与合作伙伴组织结节性硬化症协会(TSA)合作，在我们的研究过程中直接让TSC患者社区参与进来。

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.