Revolutionizing preclinical detection of risk factors for idiosyncratic drug-indu

彻底改变特殊药物行业危险因素的临床前检测

• 批准号: 7941878
• 负责人: DAVID W. THREADGILL
• 金额: $ 49.41万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941878
• 关键词: Acetaminophen; Address; Adverse event; Affect; Alanine Transaminase; Algorithms; Alleles; Amoxicillin-Potassium Clavulanate Combination; Animal Model; Architecture; Archives; Area; Biological Markers; Blood specimen; Breeding; Candidate Disease Gene; Ciprofloxacin; Clinical; Complex; Computer Simulation; Data; Detection; Development; Dose; Drug Exposure; Drug Industry; Drug Kinetics; Drug toxicity; Ethanol; Event; Failure; Floxacillin; Gene Bank; Gene Targeting; Genes; Genetic; Genetic Databases; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genetic screening method; Genome; Genomics; Goals; Hepatotoxicity; Histologic; Human; Individual; Injury; Kidney; Liver; Measurement; Minocycline; Modeling; Mouse Strains; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nitrofurantoin; Odds Ratio; Organ; Outcome; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Phenytoin; Physicians; Physiology; Plasma; Population; Preclinical Testing; Predisposition; Process; Quantitative Trait Loci; Research; Resistance; Resources; Risk; Risk Factors; Route; Safety; Scheme; Severe Adverse Event; Single Nucleotide Polymorphism; Susceptibility Gene; Tail; Testing; Toxic effect; Translating; Trimethoprim-Sulfamethoxazole; Validation; Valproic Acid; Veins; Withdrawal; abstracting; base; cost; design; drug development; drug metabolism; drug testing; experience; follow-up; genetic resource; genetic variant; genome wide association study; improved; interest; isoniazid; meetings; mouse model; patient population; pre-clinical; public health relevance; response; response to injury; safety testing; success; tool; trait; virtual

DESCRIPTION (provided by applicant): This project addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific challenge topic 03-DK-104: "Development of drug toxicity biomarkers for kidney, liver, and other organs of NIDDK interest for use in assessing human drug toxicity". Liver injury due to drug toxicity is a serious safety risk associated with drug development and poses a significant burden to physicians, the pharmaceutical industry, and regulatory agencies. Often, drug-induced liver injury (DILI) manifests as a rare, "idiosyncratic" event that occurs only in the rare, susceptible patient. This project will evaluate the use of a newly developed mouse model population, called the Collaborative Cross, to detect genetic variants that cause individuals to be susceptible to DILI. Once validated, this research tool will provide a unique means for evaluating the toxicity risk associated with pharmaceutical agents in susceptible patients as well as a means for which otherwise efficacious pharmaceutical agents may remain in public use, enabled by genetic testing. ABSTRACT Drug-induced liver injury (DILI) is the major adverse drug event that leads to regulatory actions on drugs, including failure to approve, restricted indications, and withdrawal from the marketplace. The most problematic form of DILI is "idiosyncratic", meaning the drug is safe for the vast majority of treated patients while causing catastrophic liver injury in the rare, susceptible patient. Genetic predisposition for complex traits, such as DILI, results from the combined effects of genetic variations within genes termed "quantitative trait loci" (QTL). Due to the rarity of these events, studies aimed at detection of causal risk alleles in human populations are often under-powered, thus hampering the ability to detect QTL. However, there are no animal models that have been validated for the ability to detect those genetic variants that confer an increased risk for liver toxicity for a given pharmaceutical. The project proposes a new paradigm for preclinical drug safety that is performed using a newly available mouse population, the Collaborative Cross, which was created specifically to model the genetically heterogeneous human population. The Collaborative Cross was developed using a breeding scheme that maximizes the genetic diversity between strains, allowing capture of 90% of the known genetic variation in mice. In three specific aims, our goal is to utilize the Collaborative Cross mouse population to identify genetic variants that predispose individuals for DILI. In Aim 1 - Determine the optimal drug and dose necessary to achieve a DILI response within the parental mouse strains of the Collaborative Cross - a dose- escalation study will be performed with ten drugs known to cause idiosyncratic hepatotoxicity. Phenotyping of liver injury markers will be performed to determine the optimal drug and dose needed for QTL analysis. Using the optimal drug and dose, Aim 2 - Determine genetic loci that modulate susceptibility to idiosyncratic DILI using the Collaborative Cross mouse strains - will be performed in 150 Collaborative Cross lines. These studies will utilize liver injury markers collected across the Collaborative Cross mouse population to interrogate genetic variations within the genome (i.e. single nucleotide polymorphisms; SNPs). The outcome of Aim 2 will be regions of the genome that are significantly associated with liver injury risk across mouse strains. To follow up on these studies, Aim 3 - Identify risk alleles for toxicity susceptibility within candidate gene regions - will be performed. Specific genetic variants that confer an increased risk of DILI, alone or in combination, will be identified by sequencing of target genes followed by correlation and risk ratio analysis of identified SNPs. These studies offer a unique opportunity to study the genetic architecture of predisposition to idiosyncratic DILI and have the potential to revolutionize how preclinical drug safety testing is performed. Successful completion of the proposed studies will provide a roadmap for improved drug safety testing, leading to safer drugs and a route to rescue efficacious drugs that cause toxicity in only a subset of the patient population PUBLIC HEALTH RELEVANCE: This project addresses a major challenge in the drug development process that greatly limits the utility and safety of drugs. Currently, most drugs are removed from the marketplace or are not approved for clinical use because of liver toxicity. No current platform exists to perform accurate preclinical testing of new drugs to identify those most likely to result in adverse events or to identify genetic factors that contribute to toxicity susceptibility. We are proposing a revolutionary new model based upon a mouse resource that was specifically developed to model the heterogeneous human population. The successful use of this new resource will dramatically improve drug develop, saving significant costs and greatly expanding the pharmaceutical industry.

描述（由申请人提供）：该项目涉及广泛的挑战领域 (03) 生物标志物发现和验证以及具体挑战主题 03-DK-104：“开发用于肾脏、肝脏和 NIDDK 感兴趣的其他器官的药物毒性生物标志物，用于评估人类药物毒性”。药物毒性引起的肝损伤是与药物开发相关的严重安全风险，给医生、制药行业和监管机构带来重大负担。通常，药物性肝损伤 (DILI) 表现为一种罕见的“特殊”事件，仅发生在罕见的易感患者中。该项目将评估使用新开发的小鼠模型群体（称为“协作交叉”）来检测导致个体易受 DILI 影响的遗传变异。一旦经过验证，该研究工具将提供一种独特的方法来评估与易感患者中的药剂相关的毒性风险，以及通过基因测试使原本有效的药剂可以继续在公众使用中的方法。摘要 药物性肝损伤（DILI）是主要的药物不良事件，会导致药物监管行动，包括未能批准、限制适应症和撤出市场。 DILI 最成问题的形式是“特殊的”，这意味着该药物对绝大多数接受治疗的患者来说是安全的，但会对罕见的易感患者造成灾难性的肝损伤。复杂性状（例如 DILI）的遗传易感性是由称为“数量性状基因座”（QTL）的基因内遗传变异的综合影响产生的。由于这些事件的罕见性，旨在检测人群中因果风险等位基因的研究往往力度不足，从而阻碍了检测 QTL 的能力。然而，还没有经过验证的动物模型能够检测那些导致特定药物肝毒性风险增加的遗传变异。该项目提出了一种临床前药物安全性的新范例，该范例使用新近可用的小鼠群体“协作交叉”进行，该小鼠群体是专门为模拟遗传异质性人群而创建的。 Collaborative Cross 的开发采用了一种育种方案，可最大限度地提高品系之间的遗传多样性，从而捕获小鼠 90% 的已知遗传变异。在三个具体目标中，我们的目标是利用协作交叉小鼠群体来识别导致个体易患 DILI 的遗传变异。目标 1 - 确定在协作交叉的亲代小鼠品系中实现 DILI 反应所需的最佳药物和剂量 - 将使用 10 种已知会引起特殊肝毒性的药物进行剂量递增研究。将进行肝损伤标记物的表型分析，以确定 QTL 分析所需的最佳药物和剂量。使用最佳药物和剂量，目标 2 - 使用协作交叉小鼠品系确定调节特异质 DILI 易感性的遗传位点 - 将在 150 个协作交叉系中进行。这些研究将利用从 Collaborative Cross 小鼠群体中收集的肝损伤标记物来探究基因组内的遗传变异（即单核苷酸多态性；SNP）。目标 2 的结果将是与小鼠品系肝损伤风险显着相关的基因组区域。为了跟进这些研究，将执行目标 3 - 识别候选基因区域内毒性易感性的风险等位基因。通过对目标基因进行测序，然后对已识别的 SNP 进行相关性和风险比分析，将确定单独或组合增加 DILI 风险的特定遗传变异。这些研究为研究特殊药源性肝损伤易感性的遗传结构提供了独特的机会，并有可能彻底改变临床前药物安全性测试的执行方式。拟议研究的成功完成将为改进药物安全性测试提供路线图，从而产生更安全的药物，并为挽救仅对一小部分患者群体产生毒性的有效药物提供途径 公共卫生相关性：该项目解决了药物开发过程中的一个重大挑战，该挑战极大地限制了药物的实用性和安全性。目前，大多数药物因肝毒性而被撤出市场或未获批准用于临床。目前还没有平台可以对新药进行准确的临床前测试，以识别最有可能导致不良事件的药物或识别导致毒性易感性的遗传因素。我们提出了一种基于小鼠资源的革命性新模型，该模型是专门为模拟异质人群而开发的。这种新资源的成功使用将极大地改善药物开发，节省大量成本并极大地扩展制药行业。