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

癫痫是一个主要的健康问题，在他们的一生中影响大约1/30的人。大约三分之一的癫痫患者的癫痫发作在目前的治疗中没有得到很好的控制。大约40%的癫痫患者被诊断为“全身性”癫痫（通常是遗传性癫痫），其中最有效的药物是丙戊酸钠。丙戊酸钠是一种成功的抗癫痫治疗药物已有50多年的历史，但最近，它被认为会导致出生缺陷，学习障碍和自闭症儿童在子宫内暴露于它。这导致在育龄妇女中使用丙戊酸盐受到严格限制。因此，一个关键的未满足的医学需求是开发一种耐受性良好的治疗全身性癫痫的药物，可以替代丙戊酸盐，具有相同或增强的抗癫痫活性，但不会对妊娠早期暴露于丙戊酸盐的儿童产生破坏性影响。本项目旨在满足这一需求。我们提出的解决方案是开发一种丙戊酸盐样化合物4 BCCA，这是一种非常有前途的化合物，与丙戊酸盐具有相同的抗癫痫机制，但也具有其他作用机制，这可能意味着它甚至可能比丙戊酸盐更有效。事实上，与丙戊酸盐相比，4 BCCA在多种不同的临床前动物癫痫发作模型中有效，效力和治疗指数增加。重要的是，它被特别选择，因为它缺乏丙戊酸盐对未出生婴儿的损害作用的主要分子机制之一。该项目的目的是将4 BBCA进展到首次人体试验的监管提交点。为此，我们建议确认其在癫痫发作中的有效性和无副作用，包括在预测丙戊酸盐导致出生缺陷的不良反应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，希望开发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.