Target Validation using Gene Knockouts in Somatic Cells

描述（由申请人提供）：许多人类疾病，包括癌症，没有足够的医学治疗。通常，不足不是由于药物质量差，而是由于与药物靶标相关的限制（例如，疗效不足或毒性不可接受）。因此，需要新的药物靶点来解决这些未得到满足的医疗需求。人类基因组的完整草图的可用性为发现新的和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（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，但所获得的信息只能部分识别药物靶点；他们不能预测/模拟药品的效果来证明疗效。

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.