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，都没有足够的药物治疗。通常，不足不是由于药物质量差，而是由于与药物靶点相关的限制（例如疗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。人类基因组的完整草图的可用性代表了发现药物发现和开发的新的有效靶点的巨大潜力。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）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标;它们无法预测/模拟药物产品的作用以证明疗效。 PanGenex的成立是为了利用专有的遗传技术，将人类基因组与药物发现直接联系起来。PanGenex认为，基因敲除对人类疾病属性的评估对药物的效果具有高度预测性，对成功的药物开发具有高度预测性。基因敲除的优点包括靶基因的100%失活和100%特异性。PanGenex的使命是利用其专有的遗传技术，包括基因敲除和报告技术，鉴定和分析与人类疾病有关的信号网络中的所有人类基因产物，以确定具有最佳疗效和毒性特征的药物发现目标（“治疗特征”）。 PanGenex技术的概念验证在SBIR第一阶段研究中建立。在II期研究中，将产生超过60，000个序列的敲除载体文库。从该文库中选择包含ErbB信号传导网络的基因用于基因敲除。PanGenex报告基因技术也将用于识别ErbB信号网络激活所调控的转录基因。将在胰腺癌细胞系中进行超过100个基因敲除，并用于动物模型中，以评估基因敲除对肿瘤生长延迟和肿瘤消退的影响。随后将对有效基因进行作用机制研究。还将评价敲除细胞使肿瘤细胞对胰腺癌的标准护理治疗敏感的能力。总之，这些数据证明了PanGenex技术在确定具有最佳活性的药物发现靶点方面的实用性。

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.