Target Validation using Gene Knockouts in Somatic Cells

使用体细胞中的基因敲除进行靶标验证

• 批准号: 6693992
• 负责人: Robert E Finney
• 金额: $ 18.2万
• 依托单位: PANGENEX, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-08 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6693992
• 关键词: alleles; cell line; functional /structural genomics; gel electrophoresis; gene expression; gene targeting; genetic library; genetic screening; genome; high throughput technology; molecular cloning; neoplastic growth; pancreas neoplasms; phenotype; plasmids; polymerase chain reaction; technology /technique development; transfection

DESCRIPTION (provided by applicant): Many human diseases, including cancers, have inadequate medical treatments. Often, inadequacy is not due to poor drug quality, but rather to limitations associated with the target of the drug (e.g. inadequate efficacy or unacceptable toxicity). New drug targets are therefore required to address these unmet medical needs. The availability of complete drafts of the human genome represents great potential for discovering new and effective targets for drug discovery and development. Although many descriptive technologies have been developed (e.g. expression arrays, proteomics, bio-informatics) to associate genes with human diseases, the information gained only partially identifies drug targets; they cannot predict/mimic the effects of drug products to demonstrate efficacy. PanGenex was established to exploit proprietary genetic technologies that directly tie the human genome with drug discovery. PanGenex believes that evaluation of gene knockouts on human disease attributes is highly predictive for effects of drugs and highly predictive for successful drug development. Advantages of gene knockouts include 100% inactivation of target genes with 100% specificity. PanGenex mission is to use its proprietary genetic technologies, including gene knockouts and reporter technologies, to identify and inactivate all human gene products within signaling networks relevant to human diseases to identify drug discovery targets with optimal efficacy and toxicity profiles ("therapeutic profiling"). Proof of concept for PanGenex technologies was established in SBIR Phase I studies. In Phase Il studies, a knockout vector library of over 60,000 sequences will be generated. Genes comprising the ErbB signaling network will be selected from this library for gene knockouts. PanGenex reporter technology will also be used to identify genes transcriptionally regulated by activation of the ErbB signaling network. Over 100 gene knockouts will be performed in pancreatic cancer cell lines and used in animal models to evaluate effects of gene knockouts on tumor growth delay and tumor regression. Mechanism of action studies on efficacious genes will follow. The knockout cells will also be evaluated for the ability to sensitize tumor cells to standard of care treatments for pancreatic cancer. Together, these data demonstrate the utility of PanGenex technologies to identify drug discovery targets with optimal activities.

描述(申请人提供)：许多人类疾病，包括癌症，都没有得到足够的治疗。通常，不足不是由于药物质量差，而是由于与药物目标相关的限制(例如，疗效不佳或不可接受的毒性)。因此，需要新的药物靶点来满足这些未得到满足的医疗需求。人类基因组完整草图的可获得性为发现新的有效的药物发现和开发目标提供了巨大的潜力。虽然已经开发了许多描述性技术(如表达阵列、蛋白质组学、生物信息学)来将基因与人类疾病联系起来，但获得的信息仅部分识别药物靶点；它们不能预测/模仿药物产品的效果来证明疗效。 PanGenex的成立是为了利用专利基因技术，这些技术直接将人类基因组与药物发现联系在一起。PanGenex认为，对人类疾病属性的基因敲除的评估对药物的效果和成功的药物开发具有很高的预测性。基因敲除的优点包括100%的目标基因失活和100%的特异性。PanGenex的使命是利用其专有的基因技术，包括基因敲除和报告技术，识别和灭活与人类疾病相关的信号网络中的所有人类基因产品，以确定具有最佳疗效和毒性特征的药物发现目标(“治疗概况”)。 在SBIR第一阶段研究中确立了PanGenex技术的概念验证。在Il阶段的研究中，将产生一个超过60,000个序列的敲除载体文库。组成ErbB信号网络的基因将从这个文库中挑选出来进行基因敲除。PanGenex报告技术还将用于识别由ErbB信号网络激活而转录调节的基因。将在胰腺癌细胞系中进行100多种基因敲除，并用于动物模型，以评估基因敲除对肿瘤生长延迟和肿瘤消退的影响。对有效基因的作用机制研究将随之而来。还将评估基因敲除细胞使肿瘤细胞对胰腺癌标准护理治疗敏感的能力。总而言之，这些数据证明了PanGenex技术用于识别具有最佳活动的药物发现目标。