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基因特征赋予老药新的用途

2项新的研究提出,用于治疗溃疡和癫痫发作的药物可被赋予新的用途:治疗肺癌和炎性肠病。 据估计,上市一种单一的新药平均需要花15年的时间和8亿美元的费用。 改变已经批准的药物的用途常常意味着研发者可以绕过FDA和其它监管机构要求的严格的安全性测试,从而缩短一种新药从实验室到医生诊所的时间并降低有关的成本。 过去,发现药物的新用途常常是在意外情况下发生的;例如,人们发现治疗胸痛的药物米诺地尔的一个副作用是毛发的过度生长,如今该药主要以落健的品牌用于促进头发的生长。 伟哥也有着类似的故事,这种药的研发原先是为了治疗高血压和胸痛。

如今,Atul Butte及其同事用一种根据可公开获得的分子学数据的计算方法来发现老药的新用途。 在这一研究中,Butte及其同事基于异性相吸的理念研发了一种将某种药与某种特殊疾病进行匹配的方法。 研究人员假设,通过确定某一特别药物会使某些基因被启动而某些基因被关闭,以及知道这种情况恰好是近似于某种疾病中所发生的相反情况,那么这种特别的药物或许可以帮助治疗该疾病。 该研究小组给比较过的每一对可能的药物和疾病(共有100种疾病和164种药物)的基因特征发展出了一种类似的评分。 其结果从 +1(与有关特征完全相关)至 -1(与有关特征正好相反)。 某种药物的一个类似 -1的评分预计可有效地治疗一种疾病。

研究人员接下来在实验室中检验了少许这样的疾病/药物的预测。 西咪替丁(一种预计可抗肺癌的治疗溃疡的药物)可在小鼠体内抑制肿瘤细胞;而抗癫痫药托吡酯(预计可改善炎性肠病的病情)则可在该炎性肠病的大鼠模型中减少结肠组织的损伤。 这些结果提示,这两种药物可被赋予新的用途来治疗肺癌和炎性肠病--这些疾病都需要有更好的疗法。

然而,Butte及其同事强调说,病人自己用原先治疗其它疾病的药物来自我治疗任何疾病都是错误的。 这些数据仍然是初步的,人们还需要进行临床试验来证实这些被赋予新用途的药物在人体内的功效。

一则相关的《观点栏目》讨论了赋予药物新用途的计算方法史,以及这2项研究是如何在过去的发现老药新用的方法学基础上得到提高的。

Science:基因特征赋予老药新的用途

Science:基因特征赋予老药新的用途

 

英文论文摘要:

Computational Repositioning of the Anticonvulsant Topiramate for Inflammatory Bowel Disease

ABSTRACT

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract for which there are few safe and effective therapeutic options for long-term treatment and disease maintenance. Here, we applied a computational approach to discover new drug therapies for IBD in silico, using publicly available molecular data reporting gene expression in IBD samples and 164 small-molecule drug compounds. Among the top compounds predicted to be therapeutic for IBD by our approach were prednisolone, a corticosteroid used to treat IBD, and topiramate, an anticonvulsant drug not previously described to have efficacy for IBD or any related disorders of inflammation or the gastrointestinal tract. Using a trinitrobenzenesulfonic acid (TNBS)–induced rodent model of IBD, we experimentally validated our topiramate prediction in vivo. Oral administration of topiramate significantly reduced gross pathological signs and microscopic damage in primary affected colon tissue in the TNBS-induced rodent model of IBD. These findings suggest that topiramate might serve as a therapeutic option for IBD in humans and support the use of public molecular data and computational approaches to discover new therapeutic options for disease.

Discovery and Preclinical Validation of Drug Indications Using Compendia of Public Gene Expression Data

ABSTRACT

The application of established drug compounds to new therapeutic indications, known as drug repositioning, offers several advantages over traditional drug development, including reduced development costs and shorter paths to approval. Recent approaches to drug repositioning use high-throughput experimental approaches to assess a compound’s potential therapeutic qualities. Here, we present a systematic computational approach to predict novel therapeutic indications on the basis of comprehensive testing of molecular signatures in drug-disease pairs. We integrated gene expression measurements from 100 diseases and gene expression measurements on 164 drug compounds, yielding predicted therapeutic potentials for these drugs. We recovered many known drug and disease relationships using computationally derived therapeutic potentials and also predict many new indications for these 164 drugs. We experimentally validated a prediction for the antiulcer drug cimetidine as a candidate therapeutic in the treatment of lung adenocarcinoma, and demonstrate its efficacy both in vitro and in vivo using mouse xenograft models. This computational method provides a systematic approach for repositioning established drugs to treat a wide range of human diseases.

 

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