Molecular Imaging of Targeted Cardiac Gene Therapy

心脏靶向基因治疗的分子影像

• 批准号: 8445428
• 负责人: Joseph C. Wu
• 金额: $ 38.96万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445428
• 关键词: Address; Adenovirus Vector; Adenoviruses; Adverse effects; Angiopoietins; Animal Model; Animals; Apoptosis; Area; Biodistribution; Biological; Biology; Bioluminescence; Blood Vessels; Cardiac; Cardiac Myocytes; Catheters; Cells; Chemicals; Clinical Trials; Coronary Arteriosclerosis; Coronary sinus structure; Development; Dose; Drug Kinetics; Erythropoietin; Evaluation; Fibroblast Growth Factor; Fluorescence; Future; Gene Delivery; Gene Expression; Gene Transfer; Genes; Genetic Engineering; Goals; Half-Life; Heart; Hemangioma; Hypoxia; Imaging Techniques; Imaging technology; In Vitro; Investigation; Lead; Life; Location; Mediating; Methods; Mitotic; Modeling; Modification; Molecular; Monitor; Morbidity - disease rate; Myocardial; Myocardial Ischemia; Myosin Light Chain Kinase; Non-Viral Vector; Nuclear Localization Signal; Nuclear Pore; Pathway interactions; Patients; Perfusion; Phase; Phase I Clinical Trials; Phase II/III Trial; Plasmids; Polyethylene Glycols; Positron-Emission Tomography; Pre-Clinical Model; Procollagen-Proline Dioxygenase; Recruitment Activity; Reporter Genes; Research; Research Personnel; Response Elements; Rodent; Role; Route; Safety; Side; Stem cells; Switch Genes; System; Techniques; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Transcriptional Activation; Transfection; Transgenic Animals; Translating; Translational Research; Validation; Vascular Endothelial Growth Factors; abstracting; adenoviral-mediated; angiogenesis; base; catalyst; design; gene therapy; human subject; immunogenicity; improved; in vivo; innovation; molecular imaging; mortality; novel; novel strategies; novel therapeutics; nuclease; paracrine; plasmid DNA; pre-clinical; prevent; promoter; randomized trial; research clinical testing; sound; therapeutic gene; therapeutic target; transgene expression; vector

Project Summary / Abstract Recent results from large phase II/III clinical trials on adenoviral-mediated VEGF delivery have been inconclusive if not disappointing so far. We believe a sounder strategy may be to take advantage of the HIF-1¿ upstream transcriptional regulator that can activate several downstream genes such as VEGF, FGF, IGF, angiopoietin, and erythropoietin. However, HIF-1¿ has a short biological half-life due to endogenous degradation by prolyl hydroxylase-2 (PHD2). Therefore, we hypothesize that short hairpin inhibition of PHD2 (shPHD2) represent a novel approach to induce therapeutic angiogensis. On the flip side, persistent and unregulated angiogenesis can lead to hemangioma in the heart and thus controlling gene expression in a targeted and regulatory fashion is needed. Another priority is to develop novel techniques that can be used to track gene expression in living subjects noninivasively, longitudinally, and quantitatively. Thus, the primary goal of this R01 proposal is to use our multi-disciplinary expertise in vector design, molecular imaging, vascular biology, and translational models to address the above questions. Our specific aims are to (1) develop smart vectors with robust and prolonged transgene expression, (2) monitor the pharmacokinetics and biodistribution of our novel vector in vivo, (3) demonstrate mechanisms of shPHD2 mediated gene therapy for myocardial ischemia, and (4) evaluate the safety, efficacy, and optimal delivery conditions in translational models. At the end of 5 years, we hope to translate these findings to treatment of coronary artery disease patients with our novel smart vector systems.

项目总结/摘要 最近，腺病毒介导的VEGF递送的大规模II/III期临床试验的结果已经被证实。 到目前为止还没有定论。我们认为，一个更合理的战略可能是利用 HIF-1上游转录调节因子可以激活几个下游基因，如VEGF， FGF、IGF、促血管生成素和促红细胞生成素。然而，HIF-1的生物半衰期很短， 脯氨酰羟化酶-2（PHD 2）的内源性降解。因此，我们假设短发夹 抑制PHD 2（shPHD 2）代表了诱导治疗性血管生成新方法。在另 另一方面，持续的和不受调节的血管生成可导致心脏血管瘤，从而控制 需要以靶向和调节方式的基因表达。另一个优先事项是开发新的 可用于追踪活体受试者中基因表达的非侵入性、纵向和 数量上。因此，该R 01提案的主要目标是利用我们在矢量领域的多学科专业知识 设计，分子成像，血管生物学和翻译模型，以解决上述问题 问题.我们的具体目标是（1）开发具有稳健和延长的转基因表达的智能载体， (2)监测我们的新型载体在体内的药代动力学和生物分布，（3）证明 shPHD 2介导的基因治疗心肌缺血的机制，以及（4）评估安全性， 有效性和转化模型中的最佳递送条件。5年后，我们希望 将这些发现转化为我们的新型智能载体治疗冠状动脉疾病患者 系统.