A Genetic Test for Drug-Induced Dyskinesia Risk Determination

描述（由申请人提供）：本项目的目的是开发一种涉及蛋白质RGS9的基因检测，以识别有发生迟发性运动障碍（TD）或左旋多巴诱导的运动障碍（LID）风险的患者。抗精神病药物已经彻底改变了精神分裂症和精神障碍的治疗，但“典型”抗精神病药物的使人衰弱的副作用是TD，一种病理生理学未知的不可逆运动障碍。不幸的是，第二代“非典型”抗精神病药物有其严重的心血管和糖尿病副作用。LID是用左旋多巴治疗帕金森病的一种类似的无法解释的运动副作用，其可以变得如此严重地致残，以至于否定左旋多巴治疗的任何临床益处。虽然使用多巴胺受体激动剂的帕金森病替代疗法产生较低的运动并发症发生率，但其临床疗效劣于左旋多巴。因此，有一个迫切需要的工具，以估计运动障碍的风险，在药物治疗精神病和帕金森氏病。有证据表明TD和LID的易感性中存在遗传成分，本研究的基本原理由该主要研究者和其他人最近发表的数据提供。该数据表明RGS9是TD和LID发展的关键因素，并包括以下观察结果：1）在脑中，RGS9在纹状体中特异性表达，纹状体是控制运动的基底神经节环的重要组成部分，并且在TD和LID的发展中至关重要，2）RGS9特异性调节由多巴胺受体激活的基底神经节信号传导途径，其是典型的抗精神病和抗帕金森病药物的主要靶点，和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，将检查个体患者的RGS9基因和调控区，以确定多态性（个体间DNA序列的差异）是否与TD或LID的发生相关。这些结果将用于后续阶段，以开发、验证和商业化一种有价值的临床试验，该试验可用于估计TD或LID的风险。该测试将帮助精神科医生决定使用非典型抗精神病药物治疗还是使用更便宜的典型药物，这些药物可以以长效制剂的形式给药，以增加依从性。它同样可以帮助神经科医生在治疗帕金森病时决定左旋多巴和直接多巴胺受体激动剂。运动障碍风险的估计将在开发新的抗精神病药物和抗帕金森病药物中非常有价值：通过在药物试验随机化设计中对人类受试者子集进行更好的分层，它将减少测试人群的规模，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左旋多巴的常见、严重和使人衰弱的副作用。这项研究将有助于开发一种基因测试，通过分析一种蛋白质RGS9的基因来估计患者发生这些使人衰弱的副作用的风险，这种蛋白质在药物引起的运动障碍的发展中很重要。这样的测试将允许医生通过帮助选择具有最大益处和最小危害的药物来个性化治疗。此外，估计运动障碍风险的能力将在开发新的和改进的抗精神病药和抗帕金森病药方面非常有价值。

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. 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.