drug targets | genetic | 遗传 | 药物靶点

探究遗传对寻找药物靶点的影响

 

think big

医学,肯定是以疾病为对象,每个医生都有自己专长负责的疾病,唯一的目标就是治愈或者缓解疾病。

生物医学,则是从基础研究的角度来研究疾病(表型),还有更纯粹的基础研究,都是为研究疾病做铺垫。这是市场选择的结果,医学的核心是治病,不是娱乐业让人快乐。

想象一个精密的机器,在精巧的自我运作,我们怎么拆解呢?

对比和关联(comparison and association)【DEG,GWAS,影像学,都是为了找疾病关联的signal】

实验室里没有病人,那就设计mutant,相当于破坏机器的一个部分,看机器有什么反应。

进一步深入,就要从association到causality,即解析association的具体通路。

 

一个研究的核心是提出了什么问题?这个问题有什么意义用了什么方案来解决这个问题?【方案有千万种,不必拘泥】

 

要想在科研圈立足,首先必须有自己的领域,且对该领域的核心问题有深入了解,最后有能力带领团队解决这些问题。

 

先把这个plos genetics读一下,再去读最开始的NG,了解一些最基本的概念。

All authors are employees of AbbVie.

https://www.abbvie.com/

 

drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs

用的什么样的数据来证明的?

我能想到的数据:

  human genetics evidence approved drug
gene1 1 1
gene2 1 1
gene3 0 0
gene4 1 0

 

去哪里搞这些数据呢?drugbank类似的数据库有gene-approved、failed、及其他数据,GWAScatalog里有variant-gene的数据,拿出来画个表即可,即可以算出是不是twice。

 

那再来看看这篇paper是怎么做的?

 

causal genes are clear (Mendelian traits and GWAS associations linked to coding variants),单基因病以及编码区的variant都属于比较明确的causal gene。

historical drug approvals,类似炒股预测, 能不能用历史数据来预测未来的药物成功率

assess which types of genetic evidence are most likely to be useful in guiding drug discovery,更细一点,探究哪种遗传证据更高效

We find genetic evidence from severe genetic disorders and from genetic variants that alter protein sequence is more strongly associated with historical approvals.

严重的遗传病和蛋白编码序列的变异与历史的approval有更高的相关性。

offer statistical approaches for prioritizing new drug candidates based on whether their mechanisms are supported by human genetic evidence. 提供了统计模型来预测新药的成功率

 

研究背景

每个已启动的NME的成本从30亿美元到超过100亿美元不等

only 5-10% of candidate NMEs in early-stage clinical trials are eventually approved

increasing the fraction of NMEs in development with genetic support from the current value of 15% to 50% is predicted to decrease the direct R&D cost per launched drug by 22 ± 13%

NG paper说,增加genetic support,从现在的15%增加到50%,可以减少22 ± 13%的研发支出。

leveraging genetic data to predict the success of a new drug targets【可以看看相关的研究】

genetic support也分种类,unambiguous causal genes肯定100%能让drug得到approve,那其他的genetic evidence呢?

If the association between human genetic evidence and approved drugs is genuine and continues to hold for present-day drug development, we expect better variant to gene mapping methods and more sophisticated predictive approaches will further improve our ability to prioritize drug targets. 这不就是我们正在做的工作吗,variant to gene mapping,gene prioritization

 

Nelson et al. [3] estimated a twofold increase in approval probability for Phase I drug targets with genetic evidence using drug pipeline data from Informa Pharmaprojects along with genetic data from a variety of sources, all obtained in 2013.

Phase I drug targets with genetic evidence有2倍的通过率。用的是历史数据,所以当时无法重复。

 

 

 

基本常识回顾

A Mendelian trait is one that is controlled by a single locus in an inheritance pattern. 

New molecular entities (NMEs), as defined by the FDA, are new drug products containing as their active ingredient a chemical substance marketed for the first time in the United States.

Gain-of-function Mutation. A type of mutation in which the altered gene product possesses a new molecular function or a new pattern of gene expression. Gain-of-function mutations are almost always Dominant or Semidominant.

pharmaceutical industry

quantity and quality

 

参考:

Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval

Pharmaprojects: track pharma R&D  - Informa公司主导的一个大型项目

genetic-evidence-approval - GitHub

 

The support of human genetic evidence for approved drug indications - NG - 2015

Validating therapeutic targets through human genetics - review - 2013

 

posted @ 2021-04-01 15:45  Life·Intelligence  阅读(16)  评论(0编辑  收藏
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