Sodium Channel Gene Variation in the Treatment of Epilepsy

项目摘要/摘要 超过40%的癫痫患者最初的抗癫痫治疗失败，导致显著的个人， 经济困难和社会困难。这项建议的目标是确定基因的影响 钠通道基因对卡马西平(CBZ)反应的改变 治疗癫痫。钠通道基因的单核苷酸多态(SNPs)被认为是 改变合成通道的氨基酸组成(非同义SNPs)改变通道的 对卡马西平的反应导致一些癫痫患者治疗失败。为了实现……的目标 本应用的具体目的是(1)鉴定钠通道的单核苷酸多态。 癫痫患者中枢神经系统中更常见的亚单位基因表达 对初始CBZ治疗无效的患者比对CBZ敏感的癫痫患者更有效；以及(2)确定如何 钠通道亚基基因中的SNPs影响钠的电生理和药理特性 体外通道。为了实现这些目标，钠通道基因的第一个非同义变异 对卡马西平无效的癫痫患者将被识别，这些SNPs的频率 将比较对卡马西平无效的癫痫患者、对卡马西林无效的癫痫患者 对CBZ有反应，性别和种族与对照组匹配。随后，功能后果是 这些钠通道SNPs将在体外用全细胞膜片钳技术进行研究 异源表达重组人钠通道。拟议研究的动机是 一旦了解了钠通道SNPs对CBZ反应性的影响，就会更有效 癫痫的治疗方法可以通过提供一种针对个人量身定做的预先选择治疗方法来开发 通过促进更有效的基于基因的治疗方法的发展。这项工作具有创新性 因为它将表型(卡马西平耐药癫痫)、基因型(钠通道SNPs)和功能联系在一起 (通道对AED的响应性改变)；它也是创新的，因为 药物遗传学关联研究涉及一组连续的新诊断患者服用单一 将严格评估其对治疗的反应。预计钠通道基因 多态 将被确定为临床上与CBZ失败和改变钠通道CBZ有关的疾病 响应性；这将导致一项未来的前瞻性研究，以测试CBZ响应性是否可以预测 新诊断的癫痫患者的治疗前。从功能性研究来看，体外方法用于 筛选新的抗癫痫药物是可以开发的。这些成果将产生积极影响，推动 了解一线CBZ治疗失败的原因。这一点意义重大，因为预计它将 提供更好地治疗新诊断的癫痫患者所需的信息，并将有助于未来 基因治疗方法。

PROJECT SUMMARY/ABSTRACT Initial antiepileptic treatment fails in over 40% of people with epilepsy, resulting in significant personal, financial, and societal hardships. The objective of this proposal is to determine the influence of genetic alterations in sodium channel genes on response to carbamazepine (CBZ), one of the main first line treatments for epilepsy. It is hypothesized that single nucleotide polymorphisms (SNPs) in sodium channel genes which change the amino acid composition of the resultant channel (nonsynonymous SNPs) alter the channel's responsiveness to CBZ resulting in treatment failure in some people with epilepsy. To achieve the objective of this application the specific aims are to (1) Identify single nucleotide polymorphisms in sodium channel ¿- subunit genes expressed in the central nervous system that occur more frequently in patients with epilepsy unresponsive to initial CBZ therapy than in patients with CBZ-responsive epilepsy; and (2) Determine how SNPs in sodium channel ¿-subunit genes affect electrophysiological and pharmacological properties of sodium channels in vitro. To accomplish these aims, first nonsynonymous variations in sodium channel genes occurring people with epilepsy that is unresponsive to CBZ will be identified and the frequency of these SNPs will be compared between patients with epilepsy that is unresponsive to CBZ, patients with epilepsy that responds to CBZ, and gender and ethnicity matched controls. Subsequently, the functional consequences of these sodium channel SNPs will be studied in vitro with whole cell patch clamp techniques using heterologously expressed recombinant human sodium channels. The motivation of the proposed research is that once the influence of sodium channel SNPs on CBZ responsiveness is understood, more efficacious therapies for epilepsy can be developed both by providing a way to pre-select treatment tailored to individual patients and by promoting the development of more effective genetic based therapies. This work is innovative because it links phenotype (CBZ resistant epilepsy), genotype (sodium channel SNPs) and functionality (alteration in channel responsiveness to AEDs); it is also innovative because the design of the pharmacogenetic association study involves a consecutive cohort of newly diagnosed patients taking a single AED whose response to treatment will be rigorously assessed. It is expected that sodium channel gene polymorphisms will be identified that are clinically associated with CBZ failure and alter sodium channel CBZ responsiveness; this will lead to a future prospective study to test whether CBZ responsiveness can be predict pre-treatment in patients with newly diagnosed epilepsy. From the functionality studies, in vitro methods for screening new AEDs can be developed. These results will have a positive impact by advancing understanding of how failure of first-line CBZ treatment occurs. This is significant because it is expected to provide information needed to better treat patients with newly diagnosed epilepsy and will contribute to future genetic therapeutic approaches.