Alcohol Use Disorder: Acamprosate Pharmacometabolomics-informed Pharmacogenomics

酒精使用障碍(AUD)是世界范围内一个主要的医疗和社会负担，并导致巨大的 AUD患者及其家人的痛苦。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- 阿卡米松、纳曲酮和双硫仑--已在美国获得FDA批准用于治疗AUD 只有一小部分酗酒患者对这些药物的治疗反应是通过获得 持续的禁欲。如果我们能开发出一种方法，那将是精密医学的一项重大成就 更好地对AUD患者进行个体化药物治疗，以增加AUD患者的达标率 并选择在药物治疗开始前最有可能有反应的患者。这些研究 在本申请中提出的阿卡米松将有助于推动我们实现这些目标-通过使用 阿卡米松既是一种被批准的治疗剂，也是一种治疗澳大利亚疾病的“分子探针”--我们将增加 我们对无氨基己酸酯的作用机理(S)及其潜在的病理生理学的理解 因此，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广泛经验和成功- 特别是当与基因组学和功能基因组学结合时，我们早期的氨基己酸酯临床试验 使用P20资金执行，并在此支持下提议的安慰剂对照阿卡米松试验 应用“药物代谢组学”和“药物代谢组学-信息药物基因组学” 确定阿司匹林暴露和反应的分子和基因组特征 澳元。我们还应该强调，我们建议迅速将“生物标志物”转移到功能上。 使用基于细胞系的模型验证并机械地追踪确定的基因和途径 从iPS细胞和动物模型分化出的系统和神经元-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作为 我们的主要表型，但我们也将采取类似的方法来研究其他已确定的表型。 相关性(请参阅说明)： 这种创新和全面的“多重组学”方法，基于使用氨基己酸酯作为一种 治疗剂和分子探针，将使识别分子和基因组签名成为可能 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了解 病理生理学。

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.