Replacing valproate with a safer, broad-spectrum drug for epilepsy treatment

癫痫是一个主要的健康问题，大约每30人中就有1人受到影响。大约三分之一的癫痫患者有癫痫发作，而目前的治疗方法无法很好地控制这种发作。大约40%的癫痫患者被诊断出患有全面性癫痫(通常是由基因驱动的癫痫)，其中最有效的药物是丙戊酸钠。50多年来，丙戊酸钠一直是一种成功的抗癫痫治疗方法，但最近，人们认识到，在子宫中接触丙戊酸钠会导致出生缺陷、学习障碍和自闭症。这导致丙戊酸盐在育龄妇女中的使用受到严格限制。因此，医学上一个关键的未得到满足的需求是开发一种耐受性良好的全面性癫痫治疗方法，可以用同等或增强的抗癫痫活性取代丙戊酸盐，但不会像丙戊酸盐那样对怀孕早期暴露于丙戊酸盐的儿童造成破坏性影响。该项目旨在满足这一需求。我们建议的解决方案是开发一种丙戊酸酯类化合物，4BCCA，这是一种非常有前途的化合物，具有与丙戊酸盐相同的抗癫痫机制，但也具有额外的作用机制，这可能意味着它可能比丙戊酸盐更有效。事实上，4BCCA在多种不同的临床前动物癫痫模型中都有效，与丙戊酸盐相比，其效力和治疗指数都有所提高。重要的是，之所以特别选择它，是因为它缺乏丙戊酸盐对胎儿有害影响的主要分子机制之一。该项目的目标是将4BBCA进展到监管机构提交第一个人体试验的点。为此，我们建议确认其在癫痫发作中有希望的有效性和它的副作用，包括在预测丙戊酸盐导致出生缺陷的不利影响的模型中进行更详细的评估。如果这些研究成功，那么我们将能够进行临床试验，希望能开发出一种抗癫痫药物来取代丙戊酸盐。

Epilepsy is a major health concern, affecting around 1 in 30 people in their lifetime. About one third of people with epilepsy have seizures that are not well controlled with current therapies. Approximately 40% of people with epilepsy are diagnosed with 'generalised' epilepsies (often epilepsies that are genetically driven) in which the most effective drug is sodium valproate. Sodium valproate has been a successful antiseizure treatment for over 50 years, but, more recently, it has been recognised to cause birth defects, learning disability and autism in children exposed to it in the womb. This has led to severe restrictions of valproate's use in women of child bearing age. Thus, a key unmet need in medicine is the development of a well-tolerated treatment for generalised epilepsies that can replace valproate, with equal or enhanced antiseizure activity, but without valproate's devastating effect on children exposed to it in early pregnancy. This project seeks to address this need. Our proposed solution has been to develop a valproate-like compound, 4BCCA, which is a highly promising compound, with shared antiseizure mechanisms with valproate but also with additional mechanisms of action, which may mean that it could even be more effective than valproate. Indeed, 4BCCA is effective in multiple different preclinical animal seizure models with increased potency and therapeutic index compared to valproate. Importantly, it has been particularly selected because it lacks one of the main molecular mechanisms proposed to underlie valproate's damaging effect on the unborn child. The aim of this project is to progress 4BBCA to the point of regulatory submission for first-in-human trials. To that end, we propose to confirm its promising effectiveness in seizures and its lack of side-effects, including a more detailed assessment in models which predict the adverse effects of valproate in causing birth defects. If these studies succeed, then we will be in a position to undertake clinical trials with, hopefully, the development of an antiseizure medication to replace valproate.