Advancing therapeutic discovery through phenotypic screening of the extracellular proteome using hydrodynamic intravascular injection
Advancing therapeutic discovery through phenotypic screening of the extracellular proteome using hydrodynamic intravascular injection
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DOI：
10.1517/14728222.2014.968128
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发表时间：
2014-11-01
影响因子：
5.8
通讯作者：
Li, Yang
中科院分区：
文献类型：
--
作者：
Baribault, Helene;Majeti, Jiangwen Z.;Li, Yang
目的：尽管人类基因组编码类似于2万个蛋白质编码基因，但其中只有很小一部分被探索为治疗开发的潜在靶点。近十年来，识别和验证新的蛋白质靶点的挑战导致制药工业的生产力显著下降，突出了寻找新的治疗靶点的持续需求。研究设计和方法：发现新靶点的传统方法成本高、通量低、耗时长，通常需要数年时间来验证或使靶点失效。为了解决这些局限性，作为概念的证明，我们探索了水动力尾静脉（HTV）注射作为一种基因传递方法，用于直接在体内筛选II型糖尿病治疗的新型分泌因子靶点。结果：在测试的糖尿病小鼠模型中观察到高水平和持续表达的靶蛋白，使我们能够确定多种可能调节葡萄糖代谢的新激素。结论：这些结果表明HTV是一种低成本、高通量的代谢性疾病直接体内表型药物筛选方法，也可应用于许多其他疾病领域。这种方法如果与人类基因研究等其他方法相结合，将为未来的药物发现提供重要价值。
Objective: Although the human genome encodes similar to 20,000 protein-coding genes, only a very small fraction of these have been explored as potential targets for therapeutic development. The challenge of identifying and validating new protein targets has contributed to the significant reduction in the productivity of the pharmaceutical industry in the recent decade, highlighting the continued need to find new therapeutic targets.Research design and methods: The traditional methods to discover new targets are expensive, low throughput and time consuming, usually taking years to validate or invalidate a target. To address these limitations, as a proof of concept, we explored the hydrodynamic tail vein (HTV) injection as a gene delivery method for direct in vivo phenotypic screening of novel secreted factor targets for Type II diabetes therapeutics.Results: High levels and sustained expression of target proteins were observed in diabetic mouse models tested, allowing us to identify multiple novel hormones that may regulate glucose metabolism.Conclusions: These results suggest that HTV is a low-cost, high-throughput method for direct in vivo phenotypic drug screening in metabolic disorders and could be applicable to many other disease areas as well. This method if combined with other approaches such as human genetic studies could provide a significant value to future drug discovery.