Alcohol Use Disorder: Acamprosate Pharmacometabolomics-informed Pharmacogenomics

酒精使用障碍：阿坎酸药物代谢组学信息的药物基因组学

• 批准号: 10414921
• 负责人: Richard M. Weinshilboum
• 金额: $ 56.96万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414921
• 关键词: Abstinence; Achievement; Alcoholism; Animal Model; Biological Markers; Biological Models; Cell Line; Cells; Clinical; Clinical Trials; Collaborations; Data; Development; Disease; Disease remission; Disulfiram; Drug Exposure; Family; Frequencies; Functional disorder; Funding; Future; Genes; Genomics; Goals; Instruction; Length; Major Depressive Disorder; Medical; Molecular; Molecular Probes; Molecular Profiling; Naltrexone; Neurons; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacometabolomics; Pharmacotherapy; Phenotype; Placebo Control; Placebos; Randomized; Research; Selective Serotonin Reuptake Inhibitor; Series; Signal Transduction; Study models; System; Therapeutic Agents; United States; acamprosate; alcohol abuse therapy; alcohol use disorder; base; cohort; drug action; experience; functional genomics; genome wide association study; genomic biomarker; genomic signature; induced pluripotent stem cell; innovation; metabolomics; multiple omics; placebo controlled study; precision medicine; problem drinker; recruit; response; sobriety; social; success

Alcohol use disorder (AUD) represents a major medical and social burden worldwide and results in immense suffering for AUD patients and their families. A major goal of AUD research is the development and optimization of the use of effective drugs to treat this disorder. However, only a very small number of drugs— acamprosate, naltrexone and disulfiram—have received FDA approval for the treatment of AUD in the United States, and only a small proportion of alcoholic patients respond to treatment with these agents by achieving sustained abstinence. It would be a major achievement for Precision Medicine if we were to develop ways to better individualize the drug therapy of AUD patients in order to increase the frequency of the achievement of abstinence and to select the patients most likely to respond prior to the initiation of drug therapy. The studies of acamprosate proposed in this application will help to move us toward those goals and—by using acamprosate both as an approved therapeutic agent and as a “molecular probe” for AUD--we will increase our understanding of acamprosate mechanism(s) of action and of the underlying pathophysiology of this disorder, thus helping make it possible to develop better and more effective drugs in the future. In Project 2, we will take advantage of our extensive experience and success in the application of metabolomics— particularly when joined with genomics and functional genomics, of our earlier acamprosate clinical trial performed with P20 funding and of the placebo-controlled acamprosate trial proposed with support from this application to apply “pharmacometabolomics” and “pharmacometabolomics-informed pharmacogenomics” to identify molecular and genomic signatures for acamprosate exposure and response in patients suffering from AUD. We should also emphasize that we propose to rapidly move “beyond biomarkers” to functionally validate and mechanistically pursue the genes and pathways identified by using cell line-based model systems and neurons differentiated from iPS cells as well as animal models—studies that will be conducted in close collaboration with Projects 1 and 4. As described in Project 1, we will utilize sustained abstinence as our primary phenotype, but we will also take a similar approach to study additional phenotypes identified. RELEVANCE (See instructions): This innovative and comprehensive “multiple omics” approach, based on the use of acamprosate as both a therapeutic agent and a molecular probe, will make it possible to identify molecular and genomic signatures for drug exposure and drug response while also advancing our understanding of drug action and of disease pathophysiology.

酒精使用障碍（AUD）是世界范围内的主要医疗和社会负担， 为患者及其家属带来痛苦。AUD研究的一个主要目标是开发和 优化有效药物的使用来治疗这种疾病。然而，只有极少数的药物- 阿坎酸、纳洛酮和双硫仑-已获得FDA批准用于治疗美国的AUD。 只有一小部分酒精中毒患者对这些药物的治疗有反应， 持续禁欲这将是精准医学的一项重大成就，如果我们能找到方法， 更好地个性化AUD患者的药物治疗，以增加实现的频率， 在开始药物治疗之前，选择最有可能应答的患者。研究 在本申请中提出的阿坎酸将有助于推动我们实现这些目标， 阿坎酸既作为批准的治疗剂，也作为AUD的“分子探针”--我们将增加 我们对阿坎酸的作用机制和其潜在的病理生理学的理解 这有助于在未来开发出更好、更有效的药物。在项目2中， 我们将利用我们在代谢组学应用方面的丰富经验和成功经验， 特别是当与基因组学和功能基因组学相结合时， 在P20资助下进行，并在此支持下提出了安慰剂对照阿坎酸试验。 申请将“药物代谢组学”和“药物代谢组学-知情药物基因组学”应用于 鉴定患有以下疾病的患者中阿坎酸暴露和应答的分子和基因组特征 澳元。我们还应该强调，我们建议迅速从“生物标志物”转向功能性 验证和机械地追求通过使用基于细胞系的模型识别的基因和途径 从iPS细胞分化的系统和神经元以及动物模型-将进行的研究 与项目1和项目4密切合作。如项目1所述，我们将利用持续禁欲， 我们的主要表型，但我们也将采取类似的方法来研究其他表型确定。 相关性（参见说明）： 这种创新和全面的“多组学”方法，基于使用阿坎酸作为一种药物， 治疗剂和分子探针，将使识别分子和基因组特征成为可能 药物暴露和药物反应，同时也促进了我们对药物作用和疾病的理解， 病理生理学