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: 6793746
• 负责人: Robert E Finney
• 金额: $ 39.29万
• 依托单位: XACTAGEN, LLC.
• 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 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6793746
• 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（由申请人提供）：许多人类疾病，包括癌症，都没有得到充分的治疗。通常，不足并不是由于药物质量差，而是由于与药物靶点相关的限制（例如功效不足或不可接受的毒性）。因此，需要新的药物靶点来解决这些未满足的医疗需求。人类基因组完整草图的可用性代表着发现药物发现和开发的新的有效靶点的巨大潜力。尽管已经开发了许多描述性技术（例如表达阵列、蛋白质组学、生物信息学）来将基因与人类疾病联系起来，但所获得的信息仅部分地识别药物靶标；他们无法预测/模仿药品的效果来证明功效。 PanGenex 的成立是为了利用专有的基因技术，将人类基因组与药物发现直接联系起来。 PanGenex 认为，对人类疾病属性的基因敲除评估可以高度预测药物的效果，并高度预测药物开发的成功。基因敲除的优点包括目标基因 100% 失活且具有 100% 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内的所有人类基因产物，以确定具有最佳功效和毒性特征（“治疗特征分析”）的药物发现靶点。 PanGenex 技术的概念验证是在 SBIR 第一阶段研究中建立的。在II期研究中，将生成超过60,000个序列的敲除载体库。将从该文库中选择组成 ErbB 信号网络的基因进行基因敲除。 PanGenex 报告技术还将用于识别通过激活 ErbB 信号网络进行转录调节的基因。将在胰腺癌细胞系中进行超过 100 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。随后将进行有效基因的作用机制研究。还将评估敲除细胞使肿瘤细胞对胰腺癌标准护理治疗敏感的能力。这些数据共同证明了 PanGenex 技术在识别具有最佳活性的药物发现靶点方面的实用性。