Blood Genomics of Anticonvulsant Efficacy in Children

描述(由申请人提供)： 癫痫患者的抗惊厥(AED)治疗的选择是基于患者的发作类型和AED的副作用。由于对治疗的反应存在显著的个体差异，在治疗之前或治疗早期识别谁将通过特定的AED获得长期癫痫发作自由的能力将代表着癫痫药物治疗的重大进步。我们认为，在给药前或用药后白细胞的基因组表达将识别可能获得癫痫自由的个体。我们的初步数据显示：(1)癫痫发作、中风、低血糖和低氧导致大鼠24小时后血液中基因表达的特征性变化；(2)单次癫痫发作后24小时成年患者血液中基因表达的不同变化；(3)丙戊酸和卡马西平单药治疗癫痫引起的血白细胞基因表达变化不同于每种药物，也不同于对照组。这项研究将确定是否存在与AEDs相关的血液基因组模式及其疗效。这项研究的目的将是：(1)确定奥卡西平或丙戊酸治疗6个月后癫痫发作自由的儿童是否存在独特的全血基因组表达模式；(2)确定治疗前全血中是否存在与治疗1个月或6个月癫痫发作自由相关的基因表达模式；(3)确定治疗1个月时全血中是否存在与治疗6个月癫痫发作自由相关的基因表达模式。这些假设是：(1)接受丙戊酸和奥卡西平治疗的癫痫儿童的血液基因组表达模式将彼此不同，并且与治疗前的血液样本不同。(2)治疗前或治疗一个月后白细胞中的血液基因组表达模式将预测哪些患者将在奥卡西平或丙戊酸治疗后获得癫痫缓解。我们将使用新的人类U133 Affymetrix寡核苷酸微阵列来研究全血总RNA，该微阵列评估了39,000多个转录本。

DESCRIPTION (provided by applicant): The selection of anticonvulsant (AED) therapy for patients with epilepsy is based on the patient's seizure type and AED side effect profile. Since significant individual variation exists in the response to therapy, the ability to identify, either prior to or early in therapy, individuals who will attain long-term seizure freedom with a specific AED would represent a significant advance in epilepsy pharmacotherapy. We propose that the genomic expression of white blood cells prior to or just after drug administration will identify individuals likely to attain seizure freedom. Our preliminary data shows: (1) seizures, stroke, hypoglycemia and hypoxia produce characteristic changes of gene expression in the blood of rats 24 hours later, (2) single seizures produce different changes in gene expression in the blood of adult patients 24 hours later, and (3) valproic acid and carbamazepine monotherapy in children with epilepsy produces changes of gene expression in blood leukocytes that are different for each drug and different from controls. This study will determine if there is a blood genomic pattern associated with AEDs and their efficacy. The aims of this study will be to: (1) Determine if there are unique whole blood genomic expression patterns in children with epilepsy experiencing seizure freedom six months after the initiation of oxcarbazepine or valproic acid; (2) Determine whether there is a pattern of gene expression in whole blood prior to treatment that correlates with seizure freedom at one or six months of therapy; (3) Determine if there is a pattern of gene expression in whole blood at one month of therapy that correlates with seizure freedom at six months of therapy. The hypotheses are: (1) The blood genomic expression patterns in children with epilepsy treated with valproic acid and oxcarbazepine will differ from each other and will differ from the blood samples prior to therapy (2) The blood genomic expression patterns in leukocytes prior to therapy or after one month of therapy will predict which patients will attain seizure freedom from oxcarbazepine or valproic acid therapy. We will study whole blood total RNA using the new human U133 Affymetrix oligonucleotide microarrays that assess over 39,000 transcripts.