Gene therapy for refractory epilepsy

癫痫是最常见的严重神经系统疾病，影响大约1%的人口。患有活动性癫痫的人严重扰乱了生活。他们不能开车，经历社会排斥，抑郁症和自杀率高，在癫痫发作期间有受伤甚至死亡的风险。大约四分之一的癫痫患者有癫痫发作，这是任何可用的药物都无法防止的。在许多情况下，癫痫是如此具有破坏性，以至于受影响的人愿意接受手术，切除他们大脑中产生癫痫发作的部分。即使是这种选择也只对相对较少的人开放，因为癫痫发作产生的区域远离控制运动、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)，而不仅仅是引发癫痫发作的区域。这会导致副作用，如思维过程减慢、头晕和情绪改变，这些都会阻止使用更高、可能更有效的剂量。此外，大多数治疗癫痫的药物都针对类似的机制。迫切需要以完全不同的方式治疗癫痫的新方法。我们相信，我们已经找到了一种治疗方法，这种方法可能对相当大比例的癫痫患者有效，这些人的癫痫发作是由一个可识别的大脑区域引起的。我们不是使用药物，而是在参与癫痫发作的少数神经元中添加一个基因，使它们不那么容易兴奋，从而防止癫痫发作的发生。我们为什么要进行这项工作？我们是一群基础科学家和临床医生，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，我们一直在合作开发一种对癫痫有效的基因疗法。我们发现了一种特别难以治疗的癫痫实验模型，这与许多目前没有有效治疗的人的情况相似。我们还与美国的一位合作者合作，开发了自动监测癫痫发作的新方法。我们的结果非常令人鼓舞：我们的治疗不仅阻止了癫痫的发展，而且在癫痫已经确定的情况下也逐渐停止了癫痫发作。从本质上说，我们的治疗方法可以‘治愈’癫痫，这是以前从未证明过的。这是尽管我们的治疗只针对相对较少的神经元的事实。基因疗法没有完全阻止神经元的放电，也没有可检测到的副作用，但它完全防止了癫痫发作。尽管我们的工作受到了媒体的极大关注，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。为了最大限度地提高临床试验的成功前景，我们需要提高对我们的治疗方法的理解，确保我们使用最好的基因治疗工具，并在不同的情况下对它们进行测试。我们将比较几种不同的镇静神经元的方法，以及不同的基因治疗方法。我们还将测试开启和关闭对神经元的镇静效果的方法，方法是使用基因疗法，使少量神经元对一种通常在大脑中不活跃的药物敏感，或允许短暂的光脉冲照射到大脑，以阻止选定的神经元放电。我们将对我们的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。在我们的计划结束时，加上安全性研究，我们的目标是准备开始临床试验，这将为英国数万人和世界各地数百万目前患有失控癫痫的人带来希望。

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.