Sodium Channel Gene Variation in the Treatment of Epilepsy

描述（由申请人提供）：超过40%的癫痫患者最初的抗癫痫治疗失败，导致严重的个人、经济和社会困难。这项提议的目的是确定钠通道基因的遗传改变对卡马西平（CBZ）反应的影响，卡马西平是癫痫的主要一线治疗药物之一。据推测，钠通道基因的单核苷酸多态性（snp）改变了所合成通道的氨基酸组成（非同音snp），改变了通道对CBZ的反应性，导致一些癫痫患者治疗失败。为了实现这一应用的目标，具体目标是：(1)确定在中枢神经系统中表达的钠通道a亚基基因的单核苷酸多态性，这种多态性在对CBZ治疗无反应的癫痫患者中比在CBZ反应性癫痫患者中更频繁地发生；(2)确定钠通道a亚基基因snp对钠通道体外电生理和药理学特性的影响。为了实现这些目标，首先将确定对CBZ无反应的癫痫患者钠通道基因的非同义变异，并将这些snp的频率在对CBZ无反应的癫痫患者、对CBZ有反应的癫痫患者以及性别和种族匹配的对照组之间进行比较。随后，这些钠通道snp的功能影响将在体外使用异源表达重组人钠通道的全细胞膜片钳技术进行研究。这项研究的动机是，一旦了解了钠通道snp对CBZ反应性的影响，就可以通过提供针对个体患者的预先选择治疗方法和促进更有效的基于基因的治疗方法的发展来开发更有效的癫痫治疗方法。这项工作具有创新性，因为它将表型（CBZ抗性癫痫）、基因型（钠通道snp）和功能（通道对aed的反应性改变）联系起来；它的创新之处还在于，药物遗传关联研究的设计涉及一组连续的新诊断患者，这些患者服用单一AED，对治疗的反应将被严格评估。预计钠通道基因多态性将被确定为与CBZ功能衰竭和改变钠通道CBZ反应性有关的临床基因；这将导致未来的前瞻性研究，以测试CBZ反应性是否可以预测新诊断癫痫患者的治疗前。从功能性研究中，可以开发出筛选新型抗癫痫药的体外方法。这些结果将通过促进对一线CBZ治疗失败发生的理解产生积极影响。这很重要，因为它有望提供更好地治疗新诊断癫痫患者所需的信息，并将有助于未来的遗传治疗方法。公共卫生相关性：拟议的工作与人类健康相关，因为它将促进对癫痫初始药物治疗失败的理解。因此，预计在诊断时可以确定对最常用的初始药物不太可能有反应的部分性癫痫患者，并随后对其进行个体化治疗。此外，利用本工作的结果，可以开发新的癫痫动物模型和体外筛选潜在抗癫痫药物的方法，促进新治疗方法的鉴定。

DESCRIPTION (provided by applicant): 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 a- 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 a-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. PUBLIC HEALTH RELEVANCE: The proposed work is relevant to human health because it will advance understanding of how failure of initial drug treatment for epilepsy occurs. As a result, it is anticipated that people with partial onset epilepsy who are unlikely to respond to the most commonly used initial medication could be identified at the time of diagnosis and their therapy subsequently individualized. In addition, using the results of this work, new animal models of epilepsy and in vitro methods for screening potential antiepileptic medication can be developed, facilitating identification of novel treatments.