Gene therapy for refractory epilepsy

癫痫是最常见的严重神经系统疾病，影响约1%的人口。活动性癫痫患者的生活受到严重干扰。他们不会开车，遭受社会排斥，抑郁和自杀率很高，并且在癫痫发作期间有受伤甚至死亡的风险。约四分之一的癫痫患者癫痫发作无法用任何现有药物预防。在许多情况下，癫痫是如此具有破坏性，以至于患者愿意接受手术切除导致癫痫发作的大脑部分。即使这种选择也只对相对较少的人开放，这些人的癫痫发作区域远离控制运动、语言、视觉和其他基本功能的大脑中心。大多数耐药癫痫患者没有现实的治疗选择。开发治疗癫痫的新药的主要限制是，以片剂形式服用的药物会影响整个大脑的神经细胞（神经元），而不仅仅是触发癫痫发作的区域。这会导致副作用，如思维过程变慢、头晕和情绪改变，从而阻止使用更高、可能更有效的剂量。此外，大多数用于癫痫的药物的作用机制类似。迫切需要以完全不同的方式起作用的新疗法。我们相信，我们已经找到了这样一种治疗方法，可以对很大一部分癫痫发作于可识别的大脑区域的人有效。我们没有使用药物，而是在少数与癫痫发作有关的神经元中添加一种基因，使它们不那么容易兴奋，从而防止癫痫发作。我们为什么要承担这项工作？我们是一群基础科学家和临床医生，他们对神经元如何随着癫痫的发展而变化，以及基因如何相互作用使神经元更活跃或更不活跃有深入的了解。几年来，我们一直在一起研究一种治疗癫痫的基因疗法。我们确定了一种特别难以治疗的癫痫实验模型，这与目前没有有效治疗的许多人的情况相似。我们还与美国的一位合作者合作，开发自动监测癫痫发作的新方法。我们的研究结果非常令人鼓舞：我们的治疗方法不仅可以阻止癫痫的发展，而且还可以在癫痫已经发作时逐步停止癫痫发作。从本质上讲，我们的治疗可以“治愈”癫痫，这在以前从未被证明过。尽管事实上我们的治疗只针对相对较少的神经元。基因疗法并没有完全阻止神经元放电，也没有可检测到的副作用，但它完全预防了癫痫发作。虽然我们的工作引起了媒体的极大兴趣，但我们还没有准备好开始临床试验。我们只尝试了一种癫痫的实验模型，而且只使用了两种不同的基因。为了在临床试验中取得最大的成功，我们需要提高我们对治疗方法的理解，确保我们使用了最好的基因治疗工具，并在不同的情况下进行测试。我们将比较几种不同的镇静神经元的方法，以及传递基因治疗的不同方法。我们还将测试通过基因疗法打开和关闭神经元镇静作用的方法，基因疗法使少量神经元对大脑中通常不活跃的药物敏感，或者允许短暂的光脉冲照射到大脑中，以阻止选定的神经元放电。我们将对基因疗法进行一系列越来越严格的测试，并密切关注任何可能的副作用。”到项目结束时，在安全性研究的补充下，我们的目标是准备开始临床试验，为英国数万人以及全球数百万人带来希望，这些人目前正在遭受无法控制的癫痫发作。

Epilepsy is the commonest serious neurological disorder, affecting approximately 1% of the population. People with active epilepsy have seriously disrupted lives. They cannot drive, experience social exclusion, have a high rate of depression and suicide, and are at risk of injury and even death during a seizure. About one quarter of people with epilepsy have seizures which are not prevented by any available medicines. In many cases, epilepsy is so disruptive that affected individuals are willing to undergo surgery to remove parts of their brains that generate seizures. Even this option is only open to relatively few people where the seizure-generating region is far from brain centres that control movement, language, vision and other essential functions. Most people with drug-resistant epilepsy have no realistic treatment options.The main limitation to developing new medicines to treat epilepsy is that drugs taken as tablets affect nerve cells (neurons) throughout the brain, not just in the region responsible for triggering seizures. This results in side effects such as slowed thought processes, dizziness and altered mood, which prevent higher, potentially more effective, doses from being used. Moreover, most drugs used in epilepsy target similar mechanisms. There is an urgent need for new treatments that work in completely different ways.We believe that we have found such a treatment that could be effective in a substantial proportion of people in whom seizures arise from an identifiable brain region. Instead of using drugs, we are adding a gene to a small number of neurons that are involved in seizure generation to make them less excitable, so preventing seizures from occurring.Why should we undertake this work? We are a group of basic scientists and clinicians with in-depth knowledge of how neurons change as epilepsy develops, and how genes interact to make neurons more or less active. We have worked together for several years to develop a gene therapy that works in epilepsy. We identified an experimental model of epilepsy that is particularly difficult to treat, which resembles that seen in many people who are currently without effective treatment. We also worked with a collaborator in the USA to develop new ways of monitoring seizures automatically. Our results are very encouraging: not only does our treatment stop epilepsy from developing, but it also progressively stops seizures when epilepsy is already established. In essence, our treatment can 'cure' epilepsy, which has never been demonstrated previously. This is in spite of the fact that our treatment only targets a relatively small number of neurons. Gene therapy did not completely stop neurons from firing, and had no detectable side effects, and yet it completely prevented seizures. Although our work received considerable media interest, we are not yet ready to start clinical trials. We have only tried one experimental model of epilepsy, and only using two different genes. To maximise the prospects for success in clinical trials, we need to improve our understanding of how our treatment works, ensure that we are using the best gene therapy tools, and test them in different situations. We will compare several different ways of calming neurons, and different ways of delivering the gene therapy. We will also test ways of switching on and off the calming effect on the neurons by using gene therapy that makes a small number of neurons sensitive to a drug that is normally inactive in the brain, or that allows brief pulses of light shone into the brain to stop selected neurons firing. We will put our gene therapy through a series of increasingly stringent tests, and look closely for any possible side effects.By the end of our programme, complemented by safety studies, we aim to be ready to start clinical trials, raising hope for tens of thousands of people in the UK, and millions around the world, who currently suffer from uncontrolled seizures.