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- 用于最常见形式的局灶性癫痫，颞叶癫痫（TLE）， 影响了五十万美国人尽管这个问题的规模，TLE的药物治疗失败 在这些患者中，有35%的人，留下了大量未满足的临床需求。40多年来，唯一的选择是 其中部分患者已手术切除颞叶。虽然这减少了 癫痫发作，它有很多问题。第一，它不是一种治愈方法，因此大多数患者必须继续服用抗癫痫药 有副作用的药物二、很多患者不愿意冒永久性脑溢血的风险 损害，如学习和记忆受损。TLE是癫痫的最佳研究形式之一， 有很好的TLE动物模型可用于测试新疗法。总体 这项资助的假设是，通过基因治疗沉默癫痫回路中的关键神经元， 可以有效地阻止感冒发作。这种方法可以扩展到其他类型的焦点 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， 治疗可以用于那些由于害怕神经系统疾病而无法选择手术的患者， 缺陷，具有多个癫痫灶或当焦点位于关键或“雄辩”区域时， 皮层为了解决这一关键的未满足的需求，这笔赠款将开发新的基因疗法， 重组腺相关病毒（AAV）。成像和脑电源定位方面的进展已经 使医生能够将癫痫病灶定位到细胞水平。想象一个未来， 神经外科医生注射AAV来阻止癫痫蔓延到大脑的其他部分。事实上， 磁共振成像（MRI）引导的治疗剂递送已经被证明是一种 针对特定大脑区域的有效方法。利用CURE基金会的资金， 收集的初步数据显示，修饰的渗漏K+通道（TREK-M）的AAV递送降低了 癫痫持续状态重要的是，基因治疗减少了90%的自发复发性癫痫发作， TLE大鼠模型。目的1：比较不同部位注射TREK-M，研究其对 慢性TLE大鼠模型中的自发性癫痫发作。目标2将测试基因治疗在以下方面的安全性： 对照动物以及TREK-M是否可以纠正癫痫诱导的学习和记忆缺陷。目的 3是一项临床前研究，旨在确定基因治疗对自发复发性癫痫发作的疗效 在TLE大鼠模型中。我们预测药物诱导基因治疗将对临床和基因治疗产生巨大影响。 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.