Tumor-specific gene vectors for imaging and therapy of metastatic disease

用于转移性疾病成像和治疗的肿瘤特异性基因载体

• 批准号: 8111571
• 负责人: VICTOR KRASNYKH
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111571
• 关键词: Adenovirus Vector; Adenovirus hexon capsid protein; Adenoviruses; Affect; Affinity; Animal Model; Biodistribution; Biology; Blood Vessels; Cancer Etiology; Cessation of life; Characteristics; Clinical; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Outcome; Disorder by Site; Disseminated Malignant Neoplasm; Drug Industry; Environment; Epidemiology; Gene Delivery; Gene Expression; Genes; Goals; Health; Healthcare Systems; Human; Human Adenoviruses; Hybrids; Image; Immunity; Individual; Infection; Life; Ligands; Liver; Malignant - descriptor; Malignant Neoplasms; Medicine; Modality; Modification; Molecular; Molecular Genetics; Monitor; Nature; Neoplasm Metastasis; Normal tissue morphology; Patients; Performance; Pharmaceutical Preparations; Proteins; Public Health; Recording of previous events; Regimen; Reporter Genes; Research; Seroprevalences; Serotyping; Simian Adenoviruses; Site; Specificity; Surface; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Transcriptional Activation; Transgenes; Tropism; Tumor Markers; University of Texas M D Anderson Cancer Center; Variant; Viral; Viral Vector; Virion; Virus; Work; base; clinical application; clinically relevant; conditionally replicative adenovirus; cost; design; drug development; gene function; gene therapy; high risk; human disease; improved; in vivo; malignant breast neoplasm; manufacturing process; meetings; molecular marker; novel; optical imaging; programs; prototype; receptor; receptor binding; research and development; response; success; theranostics; therapeutic gene; transgene expression; tumor; vector

DESCRIPTION (provided by applicant): Molecular-genetic imaging and gene therapy that promise to revolutionize the management of human disease are currently inefficient because available gene vectors are suboptimal for clinical use. Therefore, the long-term objective of our research program is to facilitate the development of these modalities for disseminated cancers through the design of safe and efficient dual-function gene theranostics. As an important step toward this objective, the goal of this proposed research is to explore the possibility of substantial improvement of targeted intratumoral expression of therapeutic and imaging reporter genes by developing novel viral vectors that meet the requirements of tumor-specific transduction. We hypothesize that this goal can be accomplished through rational modification of the natural tropism of simian adenovirus (Ad) Pan7, whose unique biology makes it a preferred vector prototype for genetic interventions in humans. This hypothesis will be tested by accomplishing this Specific Aim: Explore the feasibility of efficient target-specific gene delivery to disseminated tumors through the use of hexon-modified Pan7 vectors. The experimental strategy to achieve this aim is to mimic the natural mechanism of the highly efficient transduction of liver tissue in vivo described for the human Ad type 5 (Ad5), which involves numerous receptor-binding ligands anchored to the viral hexon protein. To achieve highly efficient and target-specific delivery and expression of imaging and therapeutic genes, the main protein component of the Pan7 virion, the hexon, will be genetically modified to carry ligands specific for a molecular marker of human cancers. The specificity and efficacy of the proposed vectors will be tested and compared with those of the currently used vectors in an animal model of metastatic cancer using noninvasive optical imaging facilitated by the vector-encoded reporter gene expression. By yielding dual-function gene agents that will be able to locate and selectively transduce disseminated tumor metastases on vascular delivery, this project will improve diagnosis and treatment of disseminated malignant disease, which remains the major cause of cancer-related deaths. Furthermore, the proposed gene delivery strategy is expected to be suitable for molecular-genetic imaging and therapy of a broad range of diseases and will thus have a major impact on the management of human health. The success of this proposed work will be an important contribution to the developing field of gene medicine because it will provide the field with much-needed means of gene delivery, will establish a new strategy for designing such agents, and will thus facilitate and accelerate further development of these agents toward clinical applications. PUBLIC HEALTH RELEVANCE: The proposed study has direct relevance to public health because it will yield an efficient and safe vector platform for molecular-genetic imaging and the treatment of malignant disease. Successful completion of this research will enable efficient diagnosis and therapy of metastatic cancer, thus leading to saved and prolonged human life in the subpopulation of patients with highest risk.

描述（由申请人提供）：分子遗传成像和基因疗法有望彻底改变人类疾病的治疗，因为可用的基因载体在临床上是优越的。因此，我们研究计划的长期目标是通过设计安全有效的双重功能基因theranostics来促进这些模态为传播癌症的发展。作为朝着这一目标的重要一步，这项拟议的研究的目的是探索通过开发满足肿瘤特异性转导需求的新型病毒载体，从而实现靶向肿瘤内表达和成像报告基因的可能性。 我们假设可以通过合理地修改Simian腺病毒（AD）PAN7的自然对流，其独特的生物学使其成为人类遗传干预的首选矢量原型，可以实现这一目标。该假设将通过实现这一特定目的来检验：探索通过使用己酮修饰的PAN7载体的有效靶标特异性基因传递对弥散肿瘤的可行性。实现此目的的实验策略是模仿针对人AD型5（AD5）的体内高效转导组织的自然机制，该机制涉及许多锚定在病毒hexon蛋白上的受体结合配体。为了实现成像和治疗基因的高效和特异性递送以及表达，PAN7病毒素的主要蛋白质成分，己酮，将在遗传上修饰，以携带针对人类癌的分子标记的配体。将测试所提出的载体的特异性和功效，并将使用载体编码的报告基因表达促进的非侵入性光学成像与当前使用的转移性癌动物模型进行比较。 通过产生双重功能基因剂，可以在血管递送时定位并选择性地定位并有选择地转导传播肿瘤转移，该项目将改善对传播恶性疾病的诊断和治疗，这仍然是癌症相关死亡的主要原因。此外，提出的基因输送策略有望适合分子遗传成像和多种疾病的治疗，因此将对人类健康的管理产生重大影响。 这项拟议工作的成功将是对基因医学发展领域的重要贡献，因为它将为该领域提供急需的基因输送手段，将建立新的设计这种药物的策略，从而促进和加速这些药物在临床应用方面的进一步发展。 公共卫生相关性：拟议的研究与公共卫生具有直接相关性，因为它将为分子遗传成像和对恶性疾病的治疗产生有效且安全的矢量平台。这项研究的成功完成将使转移性癌症有效地诊断和治疗，从而导致风险最高的患者亚人群中的人类延长和延长人类生命。