Integrated Strategies for Novel Treatment of Myocardial Ischemia

心肌缺血新治疗的综合策略

• 批准号: 8392100
• 负责人: Joseph C. Wu
• 金额: $ 37.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392100
• 关键词: Address; Adenovirus Vector; Adult; Animal Model; Animals; Antibiotics; Area; Autopsy; Biodistribution; Biological; Biological Assay; Biology; Bioluminescence; Blood Vessels; Cardiac; Catheters; Chronic; Clinical; Clinical Research; Clinical Trials; Coronary Arteriosclerosis; Custom; DNA; Development; Drug Kinetics; Fluorescence; Functional disorder; Future; Gadolinium; Gene Delivery; Gene Expression; Gene Transfer; Genes; Genetic Engineering; Goals; Grant; Growth; Half-Life; Heart; Heart Transplantation; Histology; Hypoxia Inducible Factor; Image; Imaging technology; Immune response; In Vitro; Infarction; Investigation; Ischemia; Lead; Left; Life; Location; Magnetic Resonance Imaging; Measures; Medical; Metabolic; Modeling; Molecular; Molecular Genetics; Monitor; Morbidity - disease rate; Myocardial Ischemia; Non-Viral Vector; PET/CT scan; Pathology; Patients; Perfusion; Phase; Phase I Clinical Trials; Phase II/III Trial; Physiology; Positron-Emission Tomography; Pre-Clinical Model; Proteomics; Protocols documentation; Recombinant DNA; Recombinants; Refractory; Replication Origin; Reporter Genes; Research Personnel; Resistance; Risk; Role; Safety; Specificity; Suggestion; Symptoms; Techniques; Therapeutic; Tissues; Transfection; Transgenes; Translating; United States; Vascular Endothelial Growth Factors; Vertebral column; angiogenesis; base; catalyst; design; gadolinium oxide; gene therapy; heart metabolism; hypoxia inducible factor 1; imaging modality; immunogenic; immunogenicity; improved; in vivo; insight; interdisciplinary approach; interest; meetings; molecular imaging; mortality; mutant; neovascularization; novel; novel strategies; pre-clinical; promoter; public health relevance; randomized trial; research clinical testing; research study; therapeutic angiogenesis; therapeutic gene; tumorigenic; vector; ventricular assist device

DESCRIPTION (provided by applicant): Coronary artery disease (CAD) is the number one cause of morbidity and mortality in the United States. Despite advances in medical therapies, some patients continue to develop refractory symptoms requiring more aggressive measures such as left ventricular assist device (LVAD) or orthotopic heart transplantation (OHT). Over the past decade, remarkable progress in recombinant DNA technology has enabled the development of molecular and cellular treatments for CAD. In particular, the field of cardiac gene therapy has evolved from in vitro studies to pre-clinical testing to multi-center trials. However, recent phase II/III trials have uncovered problems such as difficulties in controlling immunogenicity of adenoviral vectors, targeting expression to cardiac tissues, and in vivo monitoring of recombinant genes post delivery. Thus, the development of novel non-viral vectors that are safe and can yield targeted tissue delivery would be a major advance. Another significant advance will be the development of noninvasive techniques to assess gene expression, providing a new catalyst for the entire field of investigation. The aims of this proposal are to (1) develop non- immunogenic "minicircle" DNA vectors will significantly improve transfection efficiency in the heart, (2) understand the mechanisms of gene based therapy using integrated strategies of genetic and molecular assays, and (3) to evaluate the safety and efficacy in pre-clinical large animal models. At the end of 5 years, we hope to translate these findings to treatment of CAD patients with minicircle- based gene therapy in the future.

描述（由申请人提供）：冠状动脉疾病（CAD）是美国发病率和死亡率的第一名。尽管医疗疗法进展，但一些患者仍在发展难治性症状，需要采取更多积极的措施，例如左心室辅助装置（LVAD）或原位心脏移植（OHT）。在过去的十年中，重组DNA技术的显着进步使CAD的分子和细胞处理能够发展。特别是，心脏基因疗法领域已从体外研究演变为临床前测试到多中心试验。然而，最近的II/III期试验存在发现的问题，例如控制腺病毒载体的免疫原性，将表达靶向心脏组织的困难以及在分娩后重组基因的体内监测。因此，新型的非病毒载体的开发是安全的，可以产生有针对性的组织是一个重大进展。另一个重大的进步将是开发评估基因表达的无创技术，为整个研究领域提供了新的催化剂。该提案的目的是（1）开发非免疫原性的“微圆” DNA载体将显着提高心脏的转染效率，（（2）使用遗传和分子测定的集成策略，了解基于基因治疗的机制，以及（3）评估前临床大型动物的安全性和效率。在5年结束时，我们希望将这些发现转化为将来的基于微小基因疗法的CAD患者的治疗。