Sodium Channel Gene Variation in the Treatment of Epilepsy

描述(由申请人提供)：超过40%的癫痫患者的初始抗癫痫治疗失败，导致严重的个人、经济和社会困难。这项建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，卡马西平是治疗癫痫的主要一线药物之一。有人假设钠通道基因的单核苷酸多态(SNPs)改变了所产生通道的氨基酸组成(非同义SNPs)，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，具体目的是(1)确定在中枢神经系统中表达的钠通道a亚单位基因的单核苷酸多态性，这种单核苷酸多态性在对CBZ治疗无效的癫痫患者中比在CBZ敏感的癫痫患者中更常见；以及(2)确定钠通道a亚单位基因中的SNPs如何在体外影响钠通道的电生理和药理学特性。为了实现这些目标，将首先确定对CBZ无效的癫痫患者发生的钠通道基因的非同义变异，并将这些SNPs的频率在对CBZ无效的癫痫患者、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，将使用异源表达的重组人钠通道的全细胞膜片钳技术，在体外研究这些钠通道SNPs的功能后果。这项拟议研究的动机是，一旦了解了钠通道SNPs对CBZ反应性的影响，就可以通过提供一种为个别患者量身定做的预先选择治疗方法，以及通过促进更有效的基于基因的治疗的开发，来开发更有效的癫痫治疗方法。这项工作是创新的，因为它将表型(卡马西平耐药癫痫)、基因型(钠通道SNPs)和功能(通道对AED的反应性改变)联系起来；它也是创新的，因为药物遗传学关联研究的设计涉及一组连续的新诊断患者服用单一AED，其治疗反应将得到严格评估。预计钠通道基因多态性将在临床上与CBZ失效和改变钠通道CBZ反应性相关；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的癫痫患者的治疗前。通过功能研究，可以开发筛选新的AEDs的体外方法。这些结果将通过促进对一线CBZ治疗失败原因的理解而产生积极影响。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，并将有助于未来的基因治疗方法。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原因的理解。因此，预计对最常用的初始药物不太可能有反应的部分发作性癫痫患者可以在诊断时被识别出来，随后他们的治疗可以个性化。此外，利用这项工作的结果，可以开发新的癫痫动物模型和体外筛选潜在的抗癫痫药物的方法，有助于识别新的治疗方法。

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.