DNA Diagnostics for Minimizing Metabolic Side-Effects of Antipsychotics

描述（由申请人提供）：非典型抗精神病药物（AAPs）用于治疗精神分裂症、双相情感障碍、精神病性抑郁症和其他精神疾病。它们的缺点是药物引起的代谢紊乱，包括体重增加、高脂血症和糖尿病风险。这些糖尿病代谢症状（DiMS）因药物和患者而异。我们建议开发一种名为“Physiotype”的新产品，为每位患者提供有关阿立哌唑、奥氮平、喹硫平、利培酮和齐拉西酮的药物特异性风险的个性化信息。生理型由单核苷酸多态性（snp）的多基因集合组成，用生物数学算法进行解释，可以解释5种aap中DiMS的大部分个体间差异。基因组学专有的生理基因组学技术和最先进的基因分型实验室将分别通过分包合同与生活研究所（Hartford CT）和肯塔基大学（Lexington KY）的临床资源相结合。约翰·歌德博士和何塞·德莱昂博士。我们在II期的目标是发现预测这5种aap之间DiMS副作用差异的snp，并将其开发为精神科医生在实践中的预测诊断产品。我们将招募200名接受5种aap治疗的患者，描述他们的体重和脂质谱，并获得他们的DNA，以创建临床登记和DNA库。我们将确定每个患者的100000个snp基因型，涵盖所有~ 30000个基因和进化保守区域，以全面，无假设地搜索DiMS的遗传标记。在第一阶段，合作者已经积累了374名aap治疗患者及其DNA的注册表和DNA存储库。我们对来自奥氮平和利培酮治疗患者的DNA进行了基因分型，对222个心血管、代谢和精神候选基因中的384个snp进行了测序，并进行了生理基因组学预测建模。我们已经发现了奥氮平和利培酮的新型药物特异性DiMS标记，分别包括载脂蛋白E和瘦素受体基因。我们开发了一种生理型的原型，并在一个独立的精神病学人群中进行了测试。Physiotype预测，约20%的患者体重与利培酮相关，约80%的患者体重与奥氮平相关，这与已知的奥氮平平均效应一致，也指出了许多个体的利培酮特异性风险更高。在III期，所有5种aap的前瞻性随机试验计划作为FDA对Physiotype设备审查的一部分。生理型将帮助精神科医生根据每个病人的先天特征来指导药物选择，从而避免副作用，这些特征是直接从病人自己的DNA中揭示和解释的。拟议的项目将开发DNA诊断产品，以提高非典型抗精神病药物（AAPs）的安全性，并改善精神分裂症和相关疾病的医疗管理，从而获得更好的结果。到目前为止，AAP副作用的发展是不可预测的，可能会使患者致残，并阻碍患者的依从性。这些产品将使DNA指导医学成为可能：确定最适合的AAP和实施临床保障措施，针对每个患者，使用他/她的个人基因组。

DESCRIPTION (provided by applicant): Atypical antipsychotic drugs (AAPs) are indicated in the treatment for schizophrenia, bipolar disorder, psychotic depression and other psychiatric disorders. Their drawback is drug-induced metabolic derangements including weight gain, hyperlipidemia, and diabetic risks. These diabetic metabolic symptoms (DiMS) vary widely between drugs and from patient to patient. We propose to develop a novel product termed "Physiotype" to deliver personalized information for each patient on the drug- specific risks among aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone. The Physiotype consists of a multi-gene ensemble of single nucleotide polymorphisms (SNPs) that, interpreted with a biomathematical algorithm, may explain most of the inter-individual differences in DiMS among the 5 AAPs The proprietary physiogenomics technology and state-of-the-art genotyping laboratories of Genomas will be integrated with the clinical resources of the Institute of Living (Hartford CT) and of the University of Kentucky (Lexington KY), through subcontracts, respectively, to Dr. John Goethe and Dr. Jose de Leon. Our goal in Phase II is to discover SNPs predictive of differences in DiMS side effects between these 5 AAPs and to develop them into predictive diagnostic products for psychiatrists in their practice. We will recruit 200 patients treated by each of the 5 AAPs, characterize their weight and lipid profiles, and obtain their DNA for creation of a clinical registry and DNA repository. We will determine each patient's genotype at 100,000 SNPs covering all ~30,000 genes and also evolutionary conserved regions for a comprehensive, hypothesis-free search for genetic markers of DiMS. In Phase I, the collaborators have already accumulated a registry and DNA repository of 374 AAP-treated patients and their DNA. We have genotyped DNA from olanzapine- and risperidone-treated patients in the repository for an array of 384 SNPs in 222 cardiovascular, metabolic and psychiatric candidate genes and performed physiogenomic predictive modeling. We have discovered novel drug-specific DiMS markers for olanzapine and risperidone including the apolipoprotein E and leptin receptor genes, respectively. We have developed a prototype Physiotype and tested it in an independent psychiatric population. The Physiotype predicted that ~20% of patients have the most weight associated with risperidone and ~80% with olanzapine, which is consistent with known olanzapine average effects, and also pinpoints the greater risperidone-specific risk for many individuals. In Phase III, a prospective randomized trial of all 5 AAPs is planned as part of FDA review of a Physiotype device. The Physiotype will assist psychiatrists to avoid side effects by guiding drug selection for each patient according to innate characteristics unraveled and interpreted directly from the person's own DNA. The proposed program will develop DNA diagnostic products to enhance safety of atypical antipsychotic drugs (AAPs) and improve the medical management of schizophrenia and related disorders leading to better outcomes. As of now, the development of AAP side effects is unpredictable, potentially disabling to the patient, and discourages patient compliance. The products will enable DNA- guided medicine: the determination of which AAP is most suitable and the implementation of clinical safeguards, individualized to each patient, using his/her personal genome.