Mining the Genome for Therapeutic Targets
Mining the Genome for Therapeutic Targets
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DOI：
10.2337/dbi16-0069
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发表时间：
2017-07-01
期刊：
影响因子：
7.7
通讯作者：
Florez, Jose C.
中科院分区：
文献类型：
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作者：
Florez, Jose C.
目前2型糖尿病的药物选择不能治愈这种疾病。尽管有多种药物类别可有效地调节肿瘤并最大限度地减少长期并发症，但这些药物不能逆转发病机制，而且在实践中，它们不能被选择来纠正患者特异性的分子谱。制药公司发现药物开发项目越来越昂贵和繁重，许多有前途的化合物在投放市场之前就失败了。人类遗传学可以帮助推进治疗事业。基因组发现是不可知的先前存在的知识已经发现了几十个基因座，影响血糖失调。生理学研究已经开始定义疾病亚型，澄清异质性，并提出干预的分子途径。令人信服的遗传关联已经为识别表型基础的效应转录物铺平了道路，并且在选定病例中获得或丧失功能的遗传或实验证据已经阐明了指导治疗开发的效果方向。遗传学研究还可以检查脱靶效应并提供因果推断。随着这些信息的整理和广泛提供给所有利益相关者，希望它将通过加快效率，最大限度地提高成本效益和提高最终成功率来加强治疗开发管道。
Current pharmacological options for type 2 diabetes do not cure the disease. Despite the availability of multiple drug classes that modulate glycemia effectively and minimize long-term complications, these agents do not reverse pathogenesis, and in practice they are not selected to correct the molecular profile specific to the patient. Pharmaceutical companies find drug development programs increasingly costly and burdensome, and many promising compounds fail before launch to market. Human genetics can help advance the therapeutic enterprise. Genomic discovery that is agnostic to preexisting knowledge has uncovered dozens of loci that influence glycemic dysregulation. Physiological investigation has begun to define disease subtypes, clarifying heterogeneity and suggesting molecular pathways for intervention. Convincing genetic associations have paved the way for the identification of effector transcripts that underlie the phenotype, and genetic or experimental proof of gain or loss of function in select cases has clarified the direction of effect to guide therapeutic development. Genetic studies can also examine off-target effects and furnish causal inference. As this information is curated and made widely available to all stakeholders, it is hoped that it will enhance therapeutic development pipelines by accelerating efficiency, maximizing cost-effectiveness, and raising ultimate success rates.