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(申请人提供)：有望彻底改变人类疾病管理的分子遗传成像和基因疗法目前效率低下，因为现有的基因载体不适合临床使用。因此，我们研究计划的长期目标是通过设计安全有效的双功能基因治疗药物来促进这些模式的发展。作为迈向这一目标的重要一步，本研究的目标是探索通过开发满足肿瘤特异性转导要求的新型病毒载体，大幅提高治疗和成像报告基因在肿瘤内的靶向性表达的可能性。我们假设，这一目标可以通过合理修改猿腺病毒(Ad)Pan7的自然趋向性来实现，其独特的生物学特性使其成为人类遗传干预的首选载体原型。这一假设将通过实现这一特定目标来检验：探索通过使用六邻体修饰的Pan7载体有效地向播散性肿瘤运送靶向特异性基因的可行性。实现这一目标的实验策略是模仿人类Ad5(Ad5)在体内高效转导肝组织的自然机制，该机制涉及许多与病毒六邻体蛋白锚定的受体结合配体。为了实现成像和治疗基因的高效和靶向特异性传递和表达，Pan7病毒粒子的主要蛋白质成分六邻体将经过基因改造，携带人类癌症分子标记的特异性配体。利用载体编码的报告基因表达促进的非侵入性光学成像，将在转移癌动物模型中测试所建议载体的特异性和有效性，并与当前使用的载体进行比较。通过生产能够通过血管输送定位和选择性转导播散性肿瘤转移的双功能基因制剂，该项目将改善播散性恶性疾病的诊断和治疗，这种疾病仍然是与癌症相关的死亡的主要原因。此外，拟议的基因传递策略预计将适用于广泛疾病的分子遗传成像和治疗，因此将对人类健康管理产生重大影响。这项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传递手段，将建立设计此类药物的新战略，从而促进和加速这些药物向临床应用的进一步发展。 公共卫生相关性：拟议的研究与公共健康直接相关，因为它将为分子遗传成像和恶性疾病的治疗提供一个有效和安全的载体平台。这项研究的成功完成将使转移性癌症的有效诊断和治疗成为可能，从而挽救和延长高风险患者亚群的生命。