Sodium Channel Gene Variation in the Treatment of Epilepsy

项目总结/摘要 超过40%的癫痫患者的初始抗癫痫治疗失败，导致显著的个人， 经济和社会困难。这项建议的目的是确定遗传因素的影响， 钠通道基因对卡马西平（CBZ）反应的改变，卡马西平是主要的一线治疗药物之一 治疗癫痫据推测，钠通道基因的单核苷酸多态性（SNP）， 改变所得通道的氨基酸组成（非同义SNP）， 对CBZ的反应导致一些癫痫患者治疗失败。目标的实现 本申请的具体目的是（1）鉴定钠通道中的单核苷酸多态性， 在癫痫患者中更频繁发生的中枢神经系统中表达的亚单位基因 与CBZ反应性癫痫患者相比，对初始CBZ治疗无反应;（2）确定如何 钠通道<$-亚基基因的SNPs影响钠离子的电生理和药理学特性 体外通道。为了实现这些目标，首先，钠通道基因的非同义变异 将确定对CBZ无反应的癫痫患者，并确定这些SNP的频率 将在对CBZ无反应的癫痫患者、 对CBZ有反应，以及性别和种族匹配的对照。随后， 这些钠通道SNPs将在体外用全细胞膜片钳技术进行研究， 异源表达的重组人钠通道。提出研究的动机是 一旦了解钠通道SNP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预先选择适合个体的治疗方法 患者和促进更有效的基于基因的治疗的发展。这项工作是创新的 因为它将表型（CBZ耐药性癫痫）、基因型（钠通道SNP）和功能联系起来 （改变对AED的通道响应性）;它也是创新的，因为 药物遗传学关联研究涉及一个连续队列的新诊断的患者， AED对治疗的反应将被严格评估。预期钠通道基因 多态性 将确定临床上与CBZ失败相关并改变钠通道CBZ 反应性;这将导致未来的前瞻性研究，以测试是否可以预测CBZ的反应性 新诊断的癫痫患者的预治疗。根据功能性研究，体外方法用于 筛选新的AED。这些成果将通过推进 了解一线CBZ治疗失败的原因。这一点很重要，因为预计 提供所需的信息，以更好地治疗新诊断的癫痫患者，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.