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

• 批准号: 7399779
• 负责人: GUALBERTO RUANO
• 金额: $ 14.33万
• 依托单位: GENOMAS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7399779
• 关键词: Accounting; Adverse effects; Algorithms; Anti-Inflammatory Agents; Anti-inflammatory; Arts; Biometry; Blood Vessels; California; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Chromosomes; Class; Clinical; Connecticut; Coupled; Creatine Kinase; Credentialing; DNA; Diagnostic; Drug Prescriptions; Drug effect disorder; Drug usage; Elevation; End Point; Engineering; Enzymes; Expert Opinion; Fostering; Generic Drugs; Genes; Genome; Genotype; Goals; Homeostasis; Hospitals; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Individual; Institutes; Journals; LDL Cholesterol Lipoproteins; Laboratories; Link; Measurement; Medical; Mitochondria; Monitor; Muscle; Muscle Cramp; Myalgia; Myopathy; Myositis; Nerve; Numbers; Output; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacologic Substance; Pharmacology; Pharmacy facility; Phase; Physiological; Population; Predisposition; Publishing; Rate; Records; Recruitment Activity; Registries; Research; 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; Work; atorvastatin; base; cholesterol biosynthesis; clinical application; clinically relevant; college; diet and exercise; dosage; drug development; experience; novel; predictive modeling; programs; prospective; prototype; repository; response; rosuvastatin; serotonin receptor

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处方最多的药物。它们在心血管疾病一级和二级预防方面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。它们的主要临床相关安全风险是他汀类药物引起的肌病（SIM），临床上证明是一系列神经肌肉副作用（以下简称 NMSE）。 NMSE 导致 3-20% 的他汀类药物患者出现残疾，需要改变治疗方法，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] 活性升高进行监测）。 NMSE 的程度因药物和患者而异。我们将开发一种名为“SIM PhyzioType”系统的新型产品，为临床医生提供关于阿托伐他汀、辛伐他汀和瑞舒伐他汀（三种最常使用的他汀类药物）中最安全的他汀类药物的个性化信息。PhyzioType 由多 SNP（单核苷酸多态性）整体组成，通过生物数学算法进行解释，预测药物反应。 在我们的前期工作中，我们使用来自 222 个心血管和神经肌肉候选基因的 384 个 SNP 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关联。我们开发了一个原型 PhyzioType 系统，其中包含阿托伐他汀和辛伐他汀的肌痛、血清 CK 活性以及 LDLc 降低的预测模型 患者。我们发现血管稳态与 CK 升高之间以及血清素受体与肌痛之间存在机制联系。这些结果已发表在《药物基因组学》和《肌肉与神经》杂志上。对于这个 SBIR 计划，Genomas 的生理基因组学技术和最先进的基因分型实验室将与 Drs. 的临床经验和资源相结合。保罗·汤普森、吴艾伦和布鲁斯 戈登分别在哈特福德医院、大学。加州旧金山和罗戈辛研究所，通过机构分包。我们将招募 250 名接受每种药物治疗的患者，并使用现有的临床记录来表征他们的 NMSE 和 LDLc 反应。我们将使用生理基因组学来识别那些区分 3 种他汀类药物中 NMSE 风险的 SNP，并将它们组合到 SIM PhyzioType 系统中。同相 I，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，我们将采用无假设方法，通过覆盖所有染色体和线粒体上约 30,000 个基因的全基因组阵列，对每位患者进行 550,000 个 SNP 的基因分型。这项工作还将有助于 SIM 的药理学研究并揭示新的药物靶点。我们将创建并验证 SIM 卡 PhyzioType 系统可对 3 种他汀类药物中的每一种的 NMSE 和效力进行临床有用的预测。在第三阶段，计划对 SIM PhyzioType 产品进行前瞻性试验，以获得 FDA 的批准。