Pharmacogenomics in Autism Treatment

自闭症治疗中的药物基因组学

• 批准号: 7385792
• 负责人: Robert Lee Hendren
• 金额: $ 17.1万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385792
• 关键词: 18 year old; Address; Adverse effects; Aftercare; Aman; Autistic Disorder; Behavior; Behavioral; Behavioral Symptoms; Blood; Blood specimen; Brain Diseases; Child; Chin; Clinical; Development; Disease; Dose; Down Syndrome; Drowsiness; Epilepsy; Fatigue; Future; Gene Expression; Genes; Genetic Transcription; Genomics; Gilles de la Tourette syndrome; Goals; Hereditary Disease; Individual; Interferons; Lipids; Malignant Neoplasms; Methods; Migraine; Modality; Molecular Profiling; Multiple Sclerosis; Oligonucleotide Microarrays; Outcome; Patients; Pharmaceutical Preparations; Pharmacogenomics; Problem behavior; Public Health; Research; Reverse Transcriptase Polymerase Chain Reaction; Risperidone; Sampling; Tardive Dyskinesia; Tissues; Treatment Efficacy; Tuberous Sclerosis; Valproic Acid; Week; Weight Gain; Work; atypical antipsychotic; autism spectrum disorder; base; brain tissue; diabetes risk; dosage; human study; impression; improved; leukemia; response

DESCRIPTION (provided by applicant): Risperidone has been shown to be effective in decreasing serious behavioral problems in children with autism spectrum disorders (McCracken et al., 2002; Shea et al., 2004; Nagaraj et al., 2006; Pandina et al., 2006). However, only two-thirds of children respond to this treatment and many have significant side effects. Our ultimate goal for this project is to develop pretreatment methods to predict response, appropriate dosage and serious side effects of risperidone treatment. We will identify 50 children (4 to 18 years old) with autism who also have serious behavioral problems and treat them with risperidone. Blood samples will be obtained prior to treatment and after eight weeks of treatment. Treatment efficacy will be assessed using the Irritability subscale of the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement scale (CGI-I). RNA expression from blood will be assessed using Affymetrix oligonucleotide microarrays and RT-PCR. Based on preliminary studies, we expect to demonstrate a change in RNA expression in the blood of children with autism with severe behavioral problems after eight weeks of risperidone treatment compared to prior to treatment. We will determine whether those children with autism and severe behavioral problems who significantly improve by 8 weeks of risperidone treatment have different RNA expression profiles compared to children with autism whose behaviors do not improve. We will also determine whether RNA expression profiles in blood prior to treatment predict behavioral improvement or not after 8 weeks of treatment with risperidone. We will confirm the microarray results with qRT-PCR and use these to predict the risperidone responders and the risperidone non-responders in the second half of the sample to determine if specific genes do indeed predict response. The overarching hypothesis that drives this pilot R21 project is that the efficacy, dose and occurrence of side effects of risperidone for the treatment of serious behavioral symptoms in children with autism will be reflected in specific gene expression/RNA profiles in the blood prior to treatment. PUBLIC HEALTH RELEVANCE: Risperidone, the most studied atypical antipsychotic used in children, has been shown to improve severe behavioral symptoms in over half of children with autism with these problems. However, not all children with autism and severe behavioral problems respond to risperidone, and for a few, it has significant side effects. Blood genomic profiles are shown to predict medication response for disorders such as cancer and epilepsy. This re-submitted exploratory or discovery R21 study proposes to use blood genomic profiles before and after risperidone treatment in children with autism and severe behavioral problems to determine if the profiles can predict response to treatment. The ultimate goal of this line of research is to develop methods to predict which medications work for which child before initiating treatment, to predict which child might develop particular side effects, and to identify new treatment targets for future medication development.

描述（由申请人提供）：利培酮已被证明在减少患有自闭症谱系障碍的儿童的严重行为问题方面是有效的（麦克拉肯等人，2002; Shea等人，2004; Nagaraj等人，2006; Pandina等人，2006年）。然而，只有三分之二的儿童对这种治疗有反应，许多人有明显的副作用。本课题的最终目的是建立预测利培酮治疗反应、合理剂量和严重副作用的预处理方法。我们将确定50名自闭症儿童（4至18岁），他们也有严重的行为问题，并用利培酮治疗。将在给药前和给药8周后采集血样。将使用异常行为检查表（ABC）的易怒子量表和临床总体印象改善量表（CGI-I）评估治疗疗效。将使用Affyphin寡核苷酸微阵列和RT-PCR评估血液中的RNA表达。基于初步研究，我们希望证明与治疗前相比，利培酮治疗8周后，患有严重行为问题的自闭症儿童血液中RNA表达的变化。我们将确定那些患有自闭症和严重行为问题的儿童在利培酮治疗8周后显著改善，与行为没有改善的自闭症儿童相比，是否有不同的RNA表达谱。我们还将确定治疗前血液中的RNA表达谱是否预测利培酮治疗8周后的行为改善。我们将使用qRT-PCR确认微阵列结果，并使用这些结果来预测样本后半部分中利培酮反应者和利培酮无反应者，以确定特定基因是否确实预测反应。驱动这个试点R21项目的首要假设是，利培酮治疗自闭症儿童严重行为症状的疗效，剂量和副作用的发生将反映在治疗前血液中的特定基因表达/RNA谱中。公共卫生关系：利培酮是研究最多的儿童非典型抗精神病药物，已被证明可以改善超过一半的自闭症儿童的严重行为症状。然而，并不是所有患有自闭症和严重行为问题的儿童都对利培酮有反应，对少数人来说，它有明显的副作用。血液基因组图谱显示可以预测癌症和癫痫等疾病的药物反应。这项重新提交的探索性或发现性R21研究建议使用利培酮治疗自闭症和严重行为问题儿童前后的血液基因组图谱，以确定这些图谱是否可以预测对治疗的反应。这一系列研究的最终目标是开发方法，在开始治疗之前预测哪些药物对哪个孩子有效，预测哪个孩子可能会产生特定的副作用，并为未来的药物开发确定新的治疗目标。