Developing a drug-inducible gene therapy for temporal lobe epilepsy

美国有300万癫痫患者。这项研究旨在开发一流的药物-- 最常见的局灶性癫痫--颞叶癫痫(TLE)的诱导基因治疗， 这影响了50万美国人。尽管这个问题很严重，但TLE的药物治疗失败了 在其中35%的患者中，留下了大量未得到满足的临床需求。40多年来，唯一的选择就是 其中一些患者已经接受了颞叶的手术切除。尽管这会减少 癫痫，它有很多问题。其一，它不能治愈，所以大多数患者必须继续服用抗癫痫药 有副作用的药物。第二，许多患者不愿承担永久性脑损伤的风险 损害，如学习和记忆受损。TLE是研究最多的癫痫类型之一， 有很好的TLE动物模型可以用来测试新的治疗方法。最重要的是 这项拨款的假设是，通过用基因疗法使癫痫回路中的关键神经元沉默， 一个人可以有效地阻止感冒发作。这种方法可以推广到其他类型的焦点 癫痫发作，如：局灶性皮质发育不良和创伤性脑损伤后癫痫。值得注意的是，这 治疗可以用于那些由于害怕神经疾病而不能选择手术的患者 有缺陷，有多个癫痫灶，或当焦点在关键的，或口齿不清的区域时 大脑皮层。为了解决这一关键的未得到满足的需求，这笔赠款将开发新的基因疗法，其基础是 重组腺相关病毒(AAV)。成像和脑电源定位的研究进展 允许医生将癫痫灶定位到几乎细胞水平。想象一下这样的未来，而不是 在切割过程中，神经外科医生注射AAV以阻止癫痫扩散到大脑的其余部分。事实上, 磁共振成像(MRI)引导的治疗药物的交付已经被证明是一种 针对特定大脑区域的有效方法。利用治愈基金会的资金， 收集的初步数据显示，修改的泄漏K+通道(Trek-M)的AAV传递减少了 癫痫持续状态。重要的是，基因疗法将自发性反复发作减少了90%。 TLE大鼠模型。目的1比较不同部位注射Trek-M的疗效。 慢性TLE大鼠模型的自发性癫痫发作。目标2将测试基因疗法的安全性 控制动物，以及Trek-M是否可以纠正癫痫诱发的学习和记忆障碍。目标 3是一项临床前研究，旨在确定基因疗法对自发性复发性癫痫的疗效。 在TLE大鼠模型中。我们预测药物诱导的基因治疗将对这两种临床疾病产生重大影响。 和基础研究。

There are 3 million Americans with epilepsy. This research aims to develop first-in-class drug- inducible gene therapies for the most common form of focal epilepsy, temporal lobe epilepsy (TLE), which affects half a million Americans. Despite the size of this problem, medical treatment of TLE fails in 35% of these patients, leaving a large unmet clinical need. For over 40 years, the only option left for some of these patients has been surgical resection of the temporal lobe. Although this reduces seizures, it has many problems. One, it is not a cure, so most patients must continue to take antiepileptic drugs with attendant side effects. Two, many patients are unwilling to take the risk of permanent brain damage, such as impaired learning and memory. TLE is one of the best studied forms of epilepsy and there are excellent animal models of TLE that can be used to test novel therapies. The overarching hypothesis of this grant is that by silencing critical neurons in the epileptic circuit with gene therapy, one can effectively stop seizures cold. This approach could be extended to other types of focal seizures, such as: focal cortical dysplasia and epilepsy after traumatic brain injury. Notably, this treatment could be used on patients for whom surgery is not an option due to fear of neurological deficits, those with multiple seizure foci or when the focus is in a critical, or “eloquent” region of the cortex. To address this critical unmet need, this grant will develop novel gene therapies based on recombinant adeno-associated virus (AAV). Advances in imaging and EEG source localization already allow doctors to localize seizure foci almost to the cellular level. Imagine a future when, rather than cutting, neurosurgeons inject AAV to disrupt the seizure from spreading to the rest of the brain. In fact, magnetic resonance imaging (MRI)-guided delivery of therapeutics has already been shown to be an effective method for targeting specific brain regions. Using funds from the CURE Foundation, preliminary data was collected that show AAV delivery of a modified leak K+ channel (TREK-M) reduces status epilepticus. Importantly, the gene therapy reduced spontaneous recurring seizures by 90% in a rat model of TLE. Aim 1 will compare injection of TREK-M at different sites and study its effect on spontaneous seizures in a chronic TLE rat model. Aim 2 will test the safety of the gene therapy in control animals and whether TREK-M can correct seizure-induced deficits in learning and memory. Aim 3 is a preclinical study to establish the efficacy of the gene therapy on spontaneous recurring seizures in a rat model of TLE. We predict drug-inducible gene therapy will have a large impact on both clinical and basic research.