A Genetic Test for Drug-Induced Dyskinesia Risk Determination

药物引起的运动障碍风险测定的基因测试

• 批准号: 7313075
• 负责人: Abraham Kovoor
• 金额: $ 12.52万
• 依托单位: KOVOGEN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313075
• 关键词: Adverse effects; Adverse reactions; Affect; Age; Alternative Therapies; Antipsychotic Agents; Applications Grants; Award; Basal Ganglia; Behavioral; Bromocriptine; Cardiovascular Diseases; Cardiovascular system; Chronic; Complication; Corpus striatum structure; Country; DNA Sequence; Data; Delusions; Development; Disease; Dopamine Agonists; Drug-Induced Dyskinesia; Dyskinetic syndrome; Economics; Family; Functional disorder; Generations; Genes; Genetic Polymorphism; Genetic Variation; Genetic screening method; Hallucinations; Health; Homelessness; Impaired cognition; Incidence; Individual; Inferior; Life; Mental Health; Mental disorders; Motor; Movement; Movement Disorders; Muscle Rigidity; NIH Program Announcements; Neurodegenerative Disorders; Nucleic Acid Regulatory Sequences; Parkinson Disease; Patients; Pharmaceutical Preparations; Play; Population; Prevalence; Psyche structure; RGS Proteins; RNA Splicing; Research; Risk; Risk Estimate; Role; Schizophrenia; Sequence Analysis; Side; Social isolation; Societies; Stigmata; Suicide attempt; Symptoms; Tardive Dyskinesia; Testing; Thinking; Tremor; Withdrawal; abnormal involuntary movement; base; clinical efficacy; cost; diabetic; drug development; response; tool

DESCRIPTION (provided by applicant): The objective of this project is to develop a genetic test, involving the protein, RGS9, to identify patients that are at risk for developing tardive dyskinesia (TD) or L-DOPA induced dyskinesia (LID). Antipsychotic drugs have revolutionized the treatment of schizophrenia and psychotic disorders but a debilitating side-effect of "typical" antipsychotics is TD, an irreversible movement disorder of unknown pathophysiology. Unfortunately, the second generation "atypical" antipsychotics have their own serious cardiovascular and diabetic side-effects. LID is a similar unexplained motor side-effect of the treatment of Parkinson's disease with L-DOPA that can become so severely disabling as to negate any clinical benefit from L-DOPA therapy. While alternative therapy of Parkinson's disease with dopamine receptor agonists produces a lower incidence of motor complications, their clinical efficacy is inferior to L-DOPA. Thus, there is an urgent need for tools to estimate dyskinesia risk in the pharmacotherapy of both psychoses and Parkinson's disease. Evidence exists for a genetic component in the susceptibility for TD and LID and the rationale for the present investigation is provided by data recently published by this principal investigator and others. This data suggests that RGS9 is a key factor in the development of TD and LID and include the following observations: 1) in brain, RGS9 is expressed specifically in the striatum, an important component of the basal ganglia loop that controls movement and is critical in the development of TD and LID, 2) RGS9 specifically modulates basal ganglia signaling pathways activated by dopamine receptors, which are principal targets of the typical antipsychotic and antiparkinsonian drugs and 3) the RGS9 knock-out mouse is the most representative rodent model for TD and LID. In Phase 1, the RGS9 gene and regulatory regions from individual patients will be examined to determine if polymorphisms (differences in DNA sequence among individuals) can be correlated to the development of TD or LID. The results will be utilized in subsequent phases to develop, validate and commercialize a valuable clinical test that can be used to estimate the risk for developing TD or LID. The test will assist psychiatrists in deciding between treatment with atypical antipsychotics and the cheaper typical drugs which can be administered in depot formulations for increased compliance. It could similarly help neurologists decide between L-DOPA and direct dopamine receptor agonists in the therapy of Parkinson's disease. Estimation of dyskinesia risk will be very valuable in the development of new antipsychotic and antiparkinsonian drugs: by enabling better stratification of human subject subsets in drug trial randomization designs it will reduce the size of test populations, reduce risk to human subjects, lower drug development costs and ultimately lower market pricing of new drugs. Movement disorders are common, serious and debilitating side effects of antipsychotic drugs which are used to treat schizophrenia and L-DOPA which is used to treat Parkinson's disease. This research will help to develop a genetic test that will estimate the risk of a developing these debilitating side effects in a patient by analyzing the gene for a protein, RGS9, that is important in the development of drug-induced movement disorders. Such a test will allow physicians to individualize therapy by assisting in the selection of drugs with the greatest benefit and least harm. In addition, the ability to estimate dyskinesia risk will be very valuable in the development of new and improved antipsychotic and antiparkinsonian drugs.

描述（由申请人提供）：该项目的目的是开发涉及蛋白质RGS9的基因检测，以识别患有迟发性运动障碍（TD）或L-DOPA诱导的运动障碍（LID）的患者。抗精神病药已经彻底改变了精神分裂症和精神病的治疗，但“典型”抗精神病药的副作用是一种令人衰弱的副作用TD，这是一种不可逆的病理生理学的不可逆运动障碍。不幸的是，第二代“非典型”抗精神病药具有自己的严重心血管和糖尿病副作用。盖子是用L-DOPA治疗帕金森氏病的类似无法解释的运动副作用，可以变得如此严重地致残，以消除L-DOPA疗法的任何临床益处。帕金森氏病对帕金森氏病的替代疗法伴有多巴胺受体激动剂的运动并发症的发生率较低，但它们的临床功效不如L-DOPA。因此，迫切需要工具来估计精神病和帕金森氏病的药物治疗中的运动障碍风险。有证据表明，该主要研究者和其他人最近发布的数据提供了TD和LID易感性的遗传成分以及本研究的基本原理。该数据表明，RGS9是TD和LID发展的关键因素，包括以下观察结果：1）在大脑中，RGS9在纹状体中特别表达，这是基础神经节循环的重要组成部分，它控制了运动的运动，并且在TD和LID的发展中至关重要，而TD和LID的发展至关重要。典型的抗精神病药和抗帕金森药物以及3）RGS9敲除小鼠是TD和LID的最具代表性的啮齿动物模型。在第1阶段，将检查来自个别患者的RGS9基因和调节区域，以确定多态性（个体之间的DNA序列的差异）是否与TD或LID的发展有关。该结果将在随后的阶段中用于开发，验证和商业化有价值的临床测试，该测试可用于估计开发TD或LID的风险。该测试将有助于精神科医生在非典型抗精神病药和较便宜的典型药物之间做出决定，这些药物可以在仓库配方中给药以提高依从性。同样，它可以帮助神经科医生在帕金森氏病治疗中在L-DOPA和直接多巴胺受体激动剂之间做出决定。估计运动障碍风险对于新的抗精神病药和反帕金森药物的发展将非常有价值：通过在药物试验随机设计中启用人类受试者子集的更好分层，它将降低测试人群的规模，降低人类受试者的风险，降低药物开发成本，并最终降低新药的市场定价。运动障碍是常见的，严重的和使人衰弱的抗精神病药副作用，用于治疗精神分裂症和L-DOPA，用于治疗帕金森氏病。这项研究将有助于开发一种基因检测，该测试将通过分析蛋白质RGS9的基因来估计患者在患者中发展这些使人衰弱的副作用的风险，这对于药物诱导的运动障碍的发展很重要。这样的测试将使医生通过协助选择具有最大益处和最小伤害的药物来个性化治疗。此外，估计运动障碍风险的能力对于开发新的和改良的抗精神病药和反帕金森药物的能力将非常有价值。