Hitting the bullseye: finding 更好的 targets for drug development

写的:

Target identification lies at the heart of modern drug discovery. 在纸上, the process sounds simple - find a biological target that plays a role in disease, 然后找到一种与之相互作用的治疗方法——然而这掩盖了这项任务的复杂性.

发现和验证靶点的挑战反映在临床候选药物的失败率上, where promising treatments fail to show efficacy even in relatively late stage trials. 这种失败的原因通常是潜在的假设——这种药物激活或抑制一个目标，并在特定的患者群体中以特定的方式调节疾病——被证明是错误的.

而澳门第一赌城在线娱乐的管道分子从临床前研究推进到完成III期临床试验的成功率高于行业平均水平, 澳门第一赌城在线娱乐努力做得更好. 出于这个原因, 在过去的几年里，澳门第一赌城在线娱乐投资了多种技术来帮助提高目标发现. 

更多或更好的目标? 从基因型到表现型

在过去, 澳门第一赌城在线娱乐的大多数药物靶点都是通过梳理已发表的科学文献，以深入了解与疾病相关的分子途径或遗传变异而发现的. 澳门第一赌城在线娱乐现在的目标是通过澳门第一赌城在线娱乐最近在基因组学方面的投资，专注于识别原始的新目标，从而走在曲线的前面, 功能基因组学, and machine learning and artificial intelligence (ML/AI). 

发现更好靶点的旅程始于对生物学的深刻理解. 越来越多地, 这来自于基因组的见解, whether from patients and public biobanks or from tissue and tumour samples, aiming to identify genetic alterations underpinning disease. 

Through our Centre for Genomics 研究, we’re aiming to analyse 2 million genomes by 2026, drawn from diverse populations and covering a wide range of diseases and clinical trials. 

然而, 这种方法并不是挖掘基因组数据来生成更长的可能基因列表，作为药物筛选的目标. 澳门第一赌城在线娱乐不需要 更多的 目标，澳门第一赌城在线娱乐需要 更好的 的, 这不仅是为了减少药物研发的失败率，也是为了减少细胞和动物疾病模型的发现.

虽然基因组数据可以揭示与健康和疾病有关的重要基因和途径的线索, it can’t provide the full picture of what’s going on within cells, 组织, 器官或整个身体.

要做到这一点, we’re taking a 功能基因组学 approach to search for novel targets, both internally and through collaborations, such as the AstraZeneca Functional Genomics Centre with Cancer 研究 UK, and partnerships with Horizon Discovery and the Innovative Genomics Institute. 

We’re using large-scale CRISPR screens to systematically delete (CRISPRn), upregulate (CRISPRa) or downregulate (CRISPRi) every gene in the genome, looking for phenotypic outcomes that accurately mimic the desired effect of a drug. 

最终, 功能基因组学使澳门第一赌城在线娱乐能够更全面地了解基因型和表型之间的关系, to build disease-relevant models and assays for CRISPR-based or other types of screening. It underpins the discovery and validation of novel targets, 使澳门第一赌城在线娱乐能够阐明作用机制和影响疾病的生物学途径, and can also highlight potential targets for synthetic lethal approaches.

应用人工智能产生见解

如今，技术的进步和成本的下降使得对数千名患者的组织进行多组学表征——包括基因组学表征——成为可能, 转录组, 蛋白质组学, metabolomic and lipidomic analysis, 结合多模态成像和详细的临床数据-以便建立疾病状态和患者群体的表型“指纹”.

从这里, not only can we uncover pathways and targets that are responsible for driving disease, but we can spot shared mechanisms underpinning conditions with complex, 经常重叠的表型.

很多疾病，比如肝脏, kidney and heart disease are driven by common mechanisms such as inflammation, yet we try and treat them all as separate entities. We’ve been hampered in the past by approaching the science in a very siloed way, just focusing on one specific organ or disease, when in fact these conditions are linked by common biology.

由于计算机技术的进步，以这种方式分析多个复杂的数据集才成为可能. 近年来，澳门第一赌城在线娱乐看到了基于知识图谱的强大ML/AI工具的发展, which capture detailed information about objects or concepts - such as genes, 药物, diseases or molecular pathways - and the relationships between them. 

探索这种相互关联的数据空间可以产生新的见解并确定潜在的药物靶点, as well as revealing opportunities where existing 药物 might be repurposed. And although the usual caveat of data quality still applies (‘garbage in, 垃圾”), 这种做法正在取得成果. 

例如, 澳门第一赌城在线娱乐与BenevolentAI的合作已经使澳门第一赌城在线娱乐能够通过他们的知识图谱和澳门第一赌城在线娱乐丰富的数据来确定慢性肾脏疾病的新靶点. 澳门第一赌城在线娱乐现在已经开始了澳门第一赌城在线娱乐的第一个药物发现项目，这是基于一个以前未被探索和意想不到的目标，涉及肾脏足细胞功能的合作, which we validated in various preclinical models, 第二个项目即将推出.

The challenge of target validation

然而，它已被确认, 必须对任何潜在的靶点进行调查，以证明它与疾病有关，并证明调节它将产生预期的结果. 这取决于相关的，生理上现实的疾病模型和表型分析.

Today we have a range of tools and methods for generating models available to us, such as genome engineering and advanced tissue culture techniques, 创建 在活的有机体内 models with species such as zebrafish and mice or develop next-generation 在体外 基于原代细胞的模型, 诱导多能干细胞, 瀑样, 共培养, and ‘lab on a chip’ microfluidic technology.

举个例子, 如果澳门第一赌城在线娱乐要找到更有效的方法来阻止肺部疾病的发展，甚至逆转它，修复纤维化损伤, we must be able to model all parts of the lung, including the small airway epithelium, 肺泡, 成纤维细胞和免疫细胞, and combine them in both structural and functional ways to mimic the disease phenotype.

保持目标

Improving target identification and validation through the integration of genomics, 功能基因组学和ML/AI有可能在未来几年改变药物开发. Each approach individually will generate lists of targets, 但真正的力量在于确定三者之间的协同效应和共同见解. 

目前，澳门第一赌城在线娱乐投资组合中约有10%的新项目来自这些方法, and we’re aiming to make it a quarter by 2023. 在五年内，澳门第一赌城在线娱乐希望有一半的项目来自内部或合作目标发现, with physiologically-relevant validation for all of them.

与此同时，澳门第一赌城在线娱乐用于目标发现和验证的工具和技术也在不断改进, we’re also seeing a dramatic expansion in therapeutic modalities, opening up opportunities to target biological pathways in completely new ways. We have a whole toolbox of modalities, 包括细胞和基因疗法, novel antibodies and other biologics, 多肽和核酸, so we can expand the druggable space and address any target we find.

澳门第一赌城在线娱乐正在努力实现一个目标，即没有任何候选药物失败，因为它在相关的疾病模型或患者群体中不起作用. 如果澳门第一赌城在线娱乐能找到更好的靶点并提供更有可能在临床成功的药物, 澳门第一赌城在线娱乐将加快药物研发, and ultimately improve the quality of therapies and outcomes for patients.

If you’re interested in learning 更多的, listen to the latest episode of the 遗传学解压播客, where 史蒂夫•里斯 (VP Discovery Biology, Discovery Sciences, R&D, 澳门在线赌城娱乐), 大卫·戈尔茨坦(导演, 基因组医学研究所, Columbia University Medical Center, 纽约, US) and Dave Michalovich (VP Precision Medicine, BenevolentAI) talk about how we can use the power of genomics, 功能基因组学 and AI to discover new targets and make 更好的 medicines.

主题: