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DNA Diagnostic System for Statin Safety and Efficacy

他汀类药物安全性和有效性的 DNA 诊断系统

基本信息

批准号：
7616917
负责人：
GUALBERTO RUANO
金额：
$ 67.05万
依托单位：
GENOMAS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7616917
关键词：
Accounting Adverse effects Algorithms Animal Welfare Anti-Inflammatory Agents Anti-inflammatory Arts Bibliography Biometry Blood Vessels California Candidate Disease Gene Cardiovascular Diseases Cardiovascular system Chromosomes Class Clinical Connecticut Country Coupled Creatine Kinase Credentialing Crestor DNA Diagnostic Drug Prescriptions Drug effect disorder Drug usage Elevation End Point Engineering Environment Environmental Impact Enzymes Equipment Expert Opinion Fostering Generic Drugs Genes Genome Genotype Goals Homeostasis Hospitals Human Hydroxymethylglutaryl-CoA Reductase Inhibitors IACUC Individual Institutes International Journals LDL Cholesterol Lipoproteins Laboratories Link Measurement Medical Mitochondria Monitor Muscle Muscle Cramp Myalgia Myopathy Myositis Nerve Numbers Other Resources Output Pain Pathway interactions Patients Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacologic Substance Pharmacology Pharmacy facility Phase Physiological Population Predisposition Principal Investigator Publishing Rate Records Recruitment Activity Registries Research Research Ethics Committees Resources Risk Safety Sampling San Francisco Secondary Prevention Serum Simvastatin Single Nucleotide Polymorphism Site Small Business Funding Mechanisms Small Business Innovation Research Grant Syndrome System Systems Analysis Technology United States Food and Drug Administration Universities Variant Vertebrates Work abstracting atorvastatin base cholesterol biosynthesis clinical application clinically relevant college diet and exercise dosage drug development experience expiration human subject novel predictive modeling programs prospective prototype repository response rosuvastatin serotonin receptor zocor

项目摘要

DESCRIPTION (provided by applicant): Statins are the most prescribed drugs in the world. Their efficacy in primary and secondary prevention of cardiovascular disease as well as beneficial pleiotrophic and anti-inflammatory effects have fostered increasingly aggressive usage and dosage. Their main clinically relevant safety risk is statin-induced myopathy (SIM) evidenced clinically as a constellation of neuromuscular side effects (hereinafter NMSEs). NMSEs are disabling to 3-20% of patients on statins, require alteration of therapy, and reduce compliance. NMSEs include myalgias (muscle aches, cramps, weakness) and myositis (monitored by elevation of serum creatine kinase [CK] activity). NMSEs vary in extent between drugs and from patient to patient. We will develop a novel product termed SIM PhyzioType" system to provide clinicians with individualized information for each patient on the safest statin drug among atorvastatin, simvastatin, and rosuvastatin, the 3 most prescribed statins. The PhyzioType consists of a multi-SNP (single nucleotide polymorphism) ensemble that, interpreted with a biomathematical algorithm, predicts drug response. As part of our preliminary work, we have genotyped 242 statin-treated patients with a targeted array of 384 SNPs from 222 cardiovascular and neuromuscular candidate genes, and performed physiogenomic associations. We have developed a prototype PhyzioType system incorporating predictive models for myalgia, serum CK activity, and LDLc reduction for atorvastatin and simvastatin patients. We have discovered a mechanistic link between vascular homeostasis and CK elevation, and between serotonin receptors and myalgia. These results have been published in Pharmacogenomics and Muscle & Nerve. For this SBIR Program, the physiogenomics technology and state-of-the-art genotyping laboratories of Genomas will be combined with the clinical experience and resources of Drs. Paul Thompson, Alan Wu, and Bruce Gordon, respectively, at Hartford Hospital, Univ. California San Francisco and Rogosin Institute, through institutional subcontracts. We will recruit to obtain 250 patients treated with each drug and use existing clinical records to characterize their NMSE and LDLc responses. We will use physiogenomics to identify those SNPs that differentiate the risk of NMSEs among the 3 statins and combine them into the SIM PhyzioType system. In Phase I, we will continue genotyping with the hypothesis-driven array of 384 SNPs. In Phase II, we will incorporate a hypothesis-free approach by genotyping each patient at 550,000 SNPs with a total genome array covering all ~30,000 genes on all chromosomes and the mitochondrion. This work will also contribute to the pharmacology of SIM and unravel new pharmaceutical targets. We will create and validate the SIM PhyzioType system with clinically useful prediction of NMSEs and potency for each of the 3 statins. In Phase III a prospective trial is planned for FDA approval of the SIM PhyzioType product.

描述（由申请人提供）：他汀类药物是世界上最常用的处方药。它们在心血管疾病的一级和二级预防中的功效以及有益的多效性和抗炎作用促进了越来越积极的使用和剂量。其主要的临床相关安全性风险是他汀类药物诱导的肌病（SIM），临床证明为一系列神经肌肉副作用（下文称为NMSE）。NMSE使3-20%的他汀类药物患者致残，需要改变治疗，并降低依从性。NMSE包括肌痛（肌肉疼痛、痉挛、无力）和肌炎（通过血清肌酸激酶[CK]活性升高监测）。NMSE在药物之间以及患者之间的程度不同。我们将开发一种名为"SIM PhyzioType”系统的新产品，为临床医生提供关于阿托伐他汀、辛伐他汀和瑞舒伐他汀（3种最常用的他汀类药物）中最安全的他汀类药物的个体化信息。PhyzioType由多SNP（单核苷酸多态性）集合组成，该集合用生物数学算法解释，预测药物反应。作为我们初步工作的一部分，我们用来自222个心血管和神经肌肉候选基因的384个SNP的靶向阵列对242名接受他汀类药物治疗的患者进行了基因分型，并进行了生理基因组学关联。我们已经开发了一个原型PhyzioType系统，结合阿托伐他汀和辛伐他汀患者的肌痛、血清CK活性和LDL c降低的预测模型。我们已经发现了血管内稳态和CK升高之间以及5-羟色胺受体和肌痛之间的机械联系。这些结果已发表在《药理基因组学》和《肌肉与神经》上。对于这个SBIR计划，生理基因组学技术和最先进的基因分型实验室的基因组将结合博士的临床经验和资源。保罗汤普森，艾伦吴，布鲁斯戈登，分别在哈特福德医院，加州大学弗朗西斯科分校和罗戈辛研究所，通过机构分包合同。我们将招募250例接受每种药物治疗的患者，并使用现有的临床记录来表征其NMSE和LDLc反应。我们将使用生理基因组学来识别区分3种他汀类药物之间NMSE风险的SNP，并将其联合收割机组合到SIM PhyzioType系统中。在第一阶段，我们将继续使用假设驱动的384个SNP阵列进行基因分型。在第二阶段，我们将采用一种无假设的方法，对每名患者进行550，000个SNP的基因分型，总基因组阵列覆盖所有染色体和外显子上的所有~ 30，000个基因。这项工作也将有助于SIM的药理学和揭示新的药物靶点。我们将创建并验证SIM PhyzioType系统，该系统具有临床上有用的NMSE预测和3种他汀类药物的效价。在第三阶段，计划进行一项前瞻性试验，以获得FDA对SIM PhyzioType产品的批准。