A Genetic Test for Drug-Induced Dyskinesia Risk Determination

描述(申请人提供)：该项目的目标是开发一种基因测试，涉及RGS9蛋白，以确定有患迟发性运动障碍(TD)或L-多巴诱导的运动障碍(LID)的风险的患者。抗精神病药物彻底改变了精神分裂症和精神障碍的治疗方法，但“典型”抗精神病药物的副作用是TD，这是一种未知病理生理学的不可逆转的运动障碍。不幸的是，第二代“非典型”抗精神病药物有其自身严重的心血管和糖尿病副作用。LID是L多巴治疗帕金森病的一种类似的不明原因的运动副作用，可以变得如此严重，以至于否定了L多巴治疗的任何临床益处。虽然多巴胺受体激动剂替代治疗帕金森病的运动并发症发生率较低，但其临床疗效不如L多巴。因此，在精神病和帕金森病的药物治疗中，迫切需要工具来评估运动障碍的风险。有证据表明TD和LID的易感性中存在遗传成分，这一主要研究人员和其他人最近发表的数据提供了本项研究的基本原理。这些数据表明，RGS9是TD和LID发生发展中的一个关键因素，并包括下列观察结果：1)在脑中，RGS9特异地在纹状体表达，纹状体是控制运动的基础神经节回路的重要组成部分，在TD和LID的发生发展中至关重要；2)RGS9特异性调节由多巴胺受体激活的基底节信号通路，这是典型抗精神病和抗帕金森病药物的主要靶点；3)RGS9基因敲除小鼠是研究TD和LID最具代表性的啮齿动物模型。在第一阶段，将检查个体患者的RGS9基因和调节区，以确定多态(个体间DNA序列的差异)是否与TD或LID的发生相关。这些结果将在后续阶段用于开发、验证一种有价值的临床测试，并将其商业化，该测试可用于评估开发TD或LID的风险。这项测试将帮助精神科医生在非典型抗精神病药物治疗和更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使用，以提高依从性。类似地，它可以帮助神经学家在治疗帕金森病的过程中决定是使用L多巴还是直接使用多巴胺受体激动剂。运动障碍风险的评估将在新抗精神病药物和抗帕金森病药物的开发中非常有价值：通过在药物试验随机设计中更好地对人类受试者亚组进行分层，它将减少试验人群的规模，降低对人类受试者的风险，降低药物开发成本，并最终降低新药的市场定价。运动障碍是用于治疗精神分裂症的抗精神病药物和用于治疗帕金森病的L多巴的常见、严重和衰弱的副作用。这项研究将有助于开发一种基因测试，通过分析一种名为RGS9的蛋白质的基因来估计患者出现这些令人衰弱的副作用的风险，RGS9在药物诱导的运动障碍的发展中非常重要。这样的测试将允许医生通过帮助选择效益最大、危害最小的药物来实现个体化治疗。此外，评估运动障碍风险的能力将在开发新的和改进的抗精神病和抗帕金森药物方面非常有价值。

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. These data suggest 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.