英国牛津大学Julian C. Knight课题组的一项最新研究，研制了一种基因主导的方法定义了30个免疫相关性状的药物靶点等级。这一研究成果于2019年7月发表在国际顶尖学术期刊《自然—遗传学》上。

该课题组人员展示了功能基因组和免疫相关注释的集成，以及网络连接的知识，最大化基因信息用于靶标验证，在基因和通路水平上为30个免疫性状定义了靶标优先级。研究者展示了如何采用基因主导药物靶标优先级的方法(优先指标)，成功确定了当前疗法，在高通量细胞筛选中（包括L1000，CRISPR，基因诱变和病人来源细胞分析）预测细胞活性，以及优化待开发靶标，测定靶标与等级间的特征关系。优先指标是一个开放获取的、可扩展的系统，可加速免疫介导疾病的早期药物靶点筛选。

研究人员表示，目前大多数候选药物在后期临床试验中失败，很大程度上是因为对早期靶点选择的有效性预测不足。具有基因支撑的药物靶点更有可能在治疗上有效，但将基因组规模数据(如来自全基因组关联研究的数据)转化为复杂疾病中的药物靶点发现，仍然具有挑战性。

附：英文原文

Title: A genetics-led approach defines the drug target landscape of 30 immune-related traits

Author: Hai Fang, Hans De Wolf, Bogdan Knezevic, Katie L. Burnham, Julie Osgood, Anna Sanniti, Alicia Lled Lara, Silva Kasela, Stephane De Cesco, Jrg K. Wegner, Lahiru Handunnetthi, Fiona E. McCann, Liye Chen, Takuya Sekine, Paul E. Brennan, Brian D. Marsden, David Damerell, Chris A. OCallaghan, Chas Bountra, Paul Bowness, Yvonne Sundstrm, Lili Milani, Louise Berg, Hinrich W. Ghlmann, Pieter J. Peeters, Benjamin P. Fairfax, Michael Sundstrm, Julian C. Knight

Issue&Volume: Volume 51 Issue 7, July 2019

Abstract: Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection. Drug targets with genetic support are more likely to be therapeutically valid, but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging. Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach (the priority index) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets and allows for determination of target-level trait relationships. The priority index is an open-access, scalable system accelerating early-stage drug target selection for immune-mediated disease.

DOI: 10.1038/s41588-019-0456-1

Source: https://www.nature.com/articles/s41588-019-0456-1