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，包括癌症在内，医疗治疗不足。通常，不足并不是由于药物质量差，而是由于与药物靶标相关的局限性（例如功效不足或不可接受的毒性）。因此，需要新的药物目标来满足这些未满足的医疗需求。人类基因组的完整草稿的可用性代表了发现新的有效靶标的药物发现和发育目标的巨大潜力。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）将基因与人类疾病相关联，但这些信息仅部分识别药物靶标。他们无法预测/模仿药品证明功效的影响。 建立了Pangenex来利用直接将人类基因组与药物发现联系起来的专有遗传技术。 Pangenex认为，对人类疾病属性基因敲除的评估具有高度预测的药物影响，并且对成功的药物开发具有高度预测性。基因敲除的优点包括具有100％特异性的靶基因100％失活。 Pangenex的使命是使用其专有的遗传技术，包括基因敲除和记者技术，以识别和使与人类疾病相关的信号网络中的所有人类基因产物识别具有最佳功效和毒性特征的药物发现靶标（“治疗性分析”）。 在SBIR I期研究中建立了Pangenex Technologies的概念证明。在IL期研究中，将生成一个超过60,000个序列的敲除矢量库。包括ERBB信号网络的基因将从该库中选择基因敲除。 PANGENEX REPORTER技术还将用于识别通过ERBB信号网络激活在转录调节的基因。将在胰腺癌细胞系中进行超过100个基因敲除，并在动物模型中使用，以评估基因敲除对肿瘤生长延迟和肿瘤消退的影响。将随后对有效基因的作用研究。还将评估基因敲除细胞，以使肿瘤细胞对胰腺癌的护理治疗标准治疗的能力。总之，这些数据证明了Pangenex技术的实用性，以确定具有最佳活性的药物发现靶标。