A Network Approach to Gene Therapy for Refractory Epilepsies

癫痫是一种严重而常见的神经疾病，影响着全球1%的人口，尽管有最佳的药物治疗，但约三分之一的患者仍有癫痫发作。耐药癫痫患者通常不能开车，难以保住工作，抑郁和自杀的风险很高，在癫痫发作期间有摔倒、受伤甚至死亡的风险。目前，耐药手术最成功的治疗方法是切除出现癫痫发作的大脑区域。这并不是没有风险，经常会影响记忆和学习，而且往往只有部分有效。对于大多数耐药癫痫患者来说，这一选择甚至不可用，因为癫痫发作开始的大脑区域对运动、语言、记忆或视觉是必需的，或者因为癫痫发作是由大脑区域的分布式网络引起的。目前，这类患者的生活质量非常差。寻找治疗癫痫的新药不太可能取得突破。尽管在过去的30年里开发了许多新药，但癫痫的耐药率并没有改变。主要的限制是药物影响整个大脑，而不仅仅是神经元或触发癫痫的神经元电路。我们确实需要以一种完全不同的方式发挥作用的新疗法。我们是世界上致力于开发耐药癫痫基因疗法的最顶尖的科学家和临床医生团队。癫痫基因疗法的工作原理是使用超安全的病毒改变神经元的基因组成，使其不愿开火或不太可能招募下游神经元。然而，为了增加患者的成功机会，我们需要加深对癫痫发作如何发生并通过大脑传播的理解，以便确定我们的治疗目标。有时最好的方法可能是不仅治疗大脑中有可识别的结构异常的部分或可以检测到早期癫痫活动的部分，而且还治疗大脑中可以阻止癫痫蔓延的其他部分。新的小型化电子设备现在使我们能够比以前更精确地绘制癫痫发作开始的位置和发作如何传播的地图，这为治疗打开了新的可能性。我们有一系列分子工具，可以让我们安静下来，让大脑中定义的小区域安静下来，这样我们就可以确定这些区域中哪些是控制癫痫发作的最佳靶点。此外，我们还发现了新的方法，一旦癫痫发作开始，就可以抑制神经元的异常放电，使其停止在其轨道上。这项拟议的研究提出了这些相互关联的主题，我们不仅将在抑制癫痫发作方面验证进展，还将通过观察对记忆、情绪和行为的影响来验证进展。通过发现大脑中可以控制癫痫发作的新区域，我们将极大地扩大可以从基因疗法中受益的患者数量。我们的项目将扩大可用于癫痫的基因疗法的范围，并确定最有可能进入临床试验的候选药物。作为一个团队，我们已经率先进行了一项临床试验，计划于明年开始，因此在这个资金不足的生物医学领域，我们拥有将发现从替补席带到床边的可靠记录。

Epilepsy is a serious and common neurological disorder affecting up to 1% of the global population, and approximately a third of affected people continue to have seizures despite optimal medication. People with drug-resistant epilepsy typically cannot drive, have difficulties holding down jobs, have a high risk of depression and suicide, and are at risk of falls, injury and even death during a seizure. At present, the most successful treatment for drug-resistant surgery is to remove the brain area where seizures arise. This is not without risk, frequently impacts on memory and learning, and is often only partially effective. This option is not even available for the majority of patients with drug-resistant epilepsy because the brain region where seizures start is necessary for movement, language, memory or vision, or because the seizures arise from a distributed network of brain areas. Such patients currently are condemned to a very poor quality of life. The search for new drugs to treat epilepsy is unlikely to lead to a breakthrough. Despite many new medications developed in the last 30 years, the rate of drug resistance in epilepsy has not changed. The main limitation is that drugs affect the whole brain rather than just the neurons or neuronal circuits that trigger seizures. There is a real need for new treatments that work in a completely different manner.We are the world's foremost group of scientists and clinicians committed to developing gene therapy for drug-resistant epilepsy. Epilepsy gene therapy works by using ultra-safe viruses to alter the genetic make-up of neurons in order to make them reluctant to fire or less likely to recruit down-stream neurons. However, to increase the chances of success in patients, we need to deepen our understanding of how seizures arise and spread through the brain, in order to identify where to target our treatments. Sometimes the best approach may be to treat not just the part of the brain with identifiable structural abnormalities or where early seizure activity can be detected, but also other parts of the brain which can stop seizures from spreading. New miniaturised electronic devices now allow us to accurately map where seizures start and how they spread with much greater precision than we had before, and this opens new possibilities for treatments. We have a portfolio of molecular tools that allow us to quieten down small, defined regions of the brain, so that we can determine which of these areas are best targeted for controlling seizures. We have, furthermore, identified new ways to suppress the abnormal firing of neurons as soon as the seizure starts, stopping it in its tracks. The proposed research brings forward these inter-connected themes, and we will validate progress not only in terms of suppressing seizures but also by looking at effects on memory, mood and behaviour. By discovering new regions of the brain that can control seizures, we will greatly expand the number of patients who can benefit from gene therapies. Our project will broaden the repertoire of gene therapies available for epilepsy, and identify the strongest candidates to progress to clinical trials. As a team we have already pioneered a clinical trial scheduled to begin in the next year, and therefore have a proven track record of taking discoveries from the bench to the bedside in this underfunded area of biomedicine.