Transductionally Redirected and Transcriptionally Restricted Adenovirus Therapy..

转导重定向和转录限制腺病毒疗法..

• 批准号: 7991423
• 负责人: Harvey R. Herschman
• 金额: $ 15.44万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991423
• 关键词: Address; Adenovirus Vector; Adenoviruses; Adverse effects; American; Antibodies; Binding; Binding Sites; Biological Models; Blood Vessels; Cancer Model; Carcinoembryonic Antigen; Cell Culture Techniques; Cells; Cicatrix; Clinical; Clinical Trials; Colorectal Cancer; Cytomegalovirus; Diagnosis; Effectiveness; Extracellular Domain; Firefly Luciferases; Funding; Ganciclovir; Gene Delivery; Genes; Goals; Hepatic; Hepatic artery; Herpesviridae; Human; Image; Immune response; Immunity; Immunocompetent; Implant; Injection of therapeutic agent; Intravenous; Knock-out; Liver; Liver neoplasms; Luciferases; Malignant Neoplasms; Membrane; Metastatic Neoplasm to the Liver; Modeling; Modification; Monitor; Mus; Mutation; Natural Immunity; Necrosis; Neoplasm Metastasis; Normal tissue morphology; Nude Mice; Oncogenes; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Primary Neoplasm; Process; Proteins; Quantitative Evaluations; Reagent; Regulatory Element; Relative (related person); Renilla Luciferases; Reporter; Reporter Genes; Reporting; Research; Role; Solid Neoplasm; Spleen; System; Therapeutic; Time; Transgenes; Transgenic Mice; Transgenic Organisms; Translations; Tumor Burden; Virus; Xenograft procedure; adenovirus receptor; artery infusion; base; cancer cell; cyclooxygenase 2; design; gene therapy; implantation; in vivo; in vivo Cellular and Molecular Imaging Centers; intravenous administration; killings; liver function; liver xenograft; metastatic colorectal; monomer; mortality; non-invasive monitor; overexpression; promoter; therapeutic gene; therapeutic protein; thymidine kinase 1; tool; transgene expression; tumor; tumor growth; vector

Colorectal cancer (CRC) kills 50,000 Americans every year. Half have hepatic metastases at diagnosis; only a small percentage can be cured. Our overriding goal is to develop new tools to deliver therapeutic genes to hepatic CRC metastases and new tools to monitor non-invasively therapeutic gene delivery and efficacy. CRC tumors often overexpress both carcinoembryonic antigen (CEA) and cyclooxygenase 2 (COX-2). Hepatic metastases generally express even greater levels of CEA and COX-2 than their primary tumors. The aims of our currently funded Research Component 4 project are to: (1) Establish 00X2"" CEA* CRC hepatic xenografts that can be monitored by non-invasive imaging, as models of hepatic CRC metastasis. (2) Create AdCox2fLucTK, an adenovirus from which a firefly luciferase/HSVI-TK fusion reporter-therapeutic protein is regulated by the Cox2 promoter. (3) Characterize sCAR-aCEAs, adenovirus liver-untargeting/CEA* tumor-retargeting agents that fuse the Coxackie and Adenovirus Receptor (CAR) extracellular domain to a single-chain anti-CEA antibody. (4) Examine the ability of (i) sCAR-aCEA reagents to retarget Ad gene delivery vectors to CEA* CRC hepatic xenografts and the ability of (ii) Cox2 regulatory elements in Ad vectors to restrict transgene expression to COX-2* CRC xenografts, and (5) Optimize ganciclovir-dependent killing of hepatic C0X2* CEA* CRC metastases by intravenously administered, Cox2 transcriptionally restricted, transductionaily re-targeted [Ad.Cox2fLucTK][sCAR-aCEA]. We accomplished all these goals. This project received the lowest (best) priority of the current ICMIC Research Component projects. However, several criticisms from the Summary Statement form the basis of this renewal application. What are: (1) The effects of innate immunity on transductional retargeting and transcriptional restriction? (2) The effects of preexisting immunity on Ad transductional retargeting and transcriptional restriction? (3) The effects of shed, circulating soluble CEA on Ad retargeting? (4) The final criticism was a lack of a plan for clinical translation. Our Specific Aims are: (1) To establish C0X2* CEA* hepatic CRC models in immunocompetent B57BI6 and CEA-transgenic mice, and to use this model to (2) minimize the innate immune response to transcriptionally restricted/transductionally retargeted Ad imaging and therapeutic vectors, (3) optimize Ad vector evasion of neutralizing anti-ad antibody, and (4) optimize inhibition of sCAR-aCEA retargeting of Ad vectors to CEA* hepatic CRC metastases by shed CEA. (5) Our final aim is to design, develop reagents for, obtain approval for and initiate a clinical trial of Ad.Cox2HSV1sr39tk/FHBG PET imaging of CRC metastases in patients.

大肠癌（CRC）每年杀死50,000名美国人。一半在诊断时有肝转移。只能治愈一小部分。我们的压倒性目标是开发新工具，以将治疗基因运送到肝CRC转移和新工具，以监测非侵入性治疗基因的递送和功效。 CRC肿瘤经常过表达癌胚抗原（CEA）和环氧合酶2（COX-2）。 肝转移通常比其原发性肿瘤表达的CEA和COX-2水平更高。 我们当前资助的研究组件4项目的目的是：（1）建立00x2“” CEA* CRC肝异种移植物，可以通过非侵入性成像作为肝CRC转移的模型来监测。 （2）创建Adcox2fluctk，这是一种腺病毒病毒，萤火虫荧光素酶/HSVI-TK融合记者 - 治疗蛋白受到COX2启动子的调节。 （3）表征疤痕 - 阿卡西亚，腺病毒肝脏 - 未置/CEA*肿瘤 - 重捕剂，将Coxackie和腺病毒受体（CAR）融合到单链抗CEA抗体中。 (4) Examine the ability of (i) sCAR-aCEA reagents to retarget Ad gene delivery vectors to CEA* CRC hepatic xenografts and the ability of (ii) Cox2 regulatory elements in Ad vectors to restrict transgene expression to COX-2* CRC xenografts, and (5) Optimize ganciclovir-dependent killing of hepatic C0X2* CEA* CRC metastases by静脉内给药的COX2转录限制，转录日期靶向[ad.cox2fluctk] [Scar-Acea]。我们实现了所有这些目标。 该项目获得了当前ICMIC研究组件项目的最低（最佳）优先级。但是，摘要声明中的几项批评构成了本续集申请的基础。什么是：（1） 先天免疫对转移重新定位和转录限制的影响？ （2）先前存在免疫对AD转导重新定位和转录限制的影响？ （3）棚屋，循环可溶性CEA对AD重新定位的影响？ （4）最终的批评是缺乏临床翻译计划。 我们的具体目的是：（1）在免疫功能的B57BI6和CEA-转基因小鼠中建立C0x2* CEA*肝CRC模型，并使用该模型来（2）最小化转录/经dragtionctition traggation trablectib dectib and Traperib and Traperiag和Therapedor的统治供应（3）的统治，（3）最小化的免疫反应（3） （4）优化通过SHED CEA对AD载体对CEA*肝CRC转移量的疤痕添加抑制作用。 （5）我们的最终目的是设计，开发试剂供ad.cox2hsv1sr39tk/fhbg pet pet的临床试验。