Molecular Imaging of Targeted Cardiac Gene Therapy

心脏靶向基因治疗的分子影像

• 批准号: 8282999
• 负责人: Joseph C. Wu
• 金额: $ 0.28万
• 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/8282999
• 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; Health; 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 Agents; Tissues; Toxic effect; Transcriptional Activation; Transfection; Transgenic Animals; Translating; Translational Research; Validation; Vascular Endothelial Growth Factors; 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 angiogenesis; therapeutic gene; therapeutic target; transgene expression; vector

DESCRIPTION (provided by applicant): 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-11 upstream transcriptional regulator that can activate several downstream genes such as VEGF, FGF, IGF, angiopoietin, and erythropoietin. However, HIF-11 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 angiogenesis. 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 noninvasively, 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. PUBLIC HEALTH RELEVANCE: Although initial phase 1 trials in patients with myocardial ischemia provided encouraging results, recent phase 2 randomized trials (AGENT, VIVA, KAT) yielded only modest benefits. These inconsistencies have been attributed to lack of ideal delivery vectors, unclear role of single therapeutic gene such as VEGF, suboptimal dosing or route of administration, and inability to monitor gene transfer in patients. For the field to move forward, the pressing questions that need to be resolved are: (i) finding a suitable vector to overcome physical barriers, (ii) develop a novel method mean to verify gene expression in vivo, (iii) dissect the molecular mechanisms of gene therapy, and (iv) demonstrate safety and efficacy in translational models. The significance of this R01 proposal is to validate that chemical conjugation can be used to significantly improve the transfection efficiency of plasmid DNA, that novel molecular imaging platforms will allow us to monitor the pharmacokinetics and biodistribution of gene therapy in living subjects, that a "smart vector system" can be designed to be tissue specific and hypoxia responsive, and finally that gene therapy can be used in small animals, large animals, and human subjects in the future.

描述（由申请人提供）：关于腺病毒介导的 VEGF 递送的大型 II/III 期临床试验的最新结果即使不是令人失望，也尚无定论。我们认为，更合理的策略可能是利用 HIF-11 上游转录调节因子，它可以激活多个下游基因，如 VEGF、FGF、IGF、血管生成素和促红细胞生成素。然而，由于脯氨酰羟化酶 2 (PHD2) 的内源性降解，HIF-11 的生物半衰期较短。因此，我们假设 PHD2 的短发夹抑制 (shPHD2) 代表了一种诱导治疗性血管生成的新方法。另一方面，持续且不受调节的血管生成可能导致心脏血管瘤，因此需要以靶向和调节的方式控制基因表达。另一个优先事项是开发可用于无创、纵向和定量追踪活体受试者基因表达的新技术。因此，R01提案的主要目标是利用我们在载体设计、分子成像、血管生物学和转化模型方面的多学科专业知识来解决上述问题。我们的具体目标是（1）开发具有强大和持久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shPHD2介导的心肌缺血基因治疗机制，以及（4 ）评估转化模型中的安全性、有效性和最佳递送条件。 5 年后，我们希望利用我们的新型智能载体系统将这些发现转化为冠状动脉疾病患者的治疗。公众健康相关性：尽管针对心肌缺血患者的初始 1 期试验提供了令人鼓舞的结果，但最近的 2 期随机试验（AGENT、VIVA、KAT）仅产生了适度的益处。这些不一致的原因是缺乏理想的递送载体、单一治疗基因（例如 VEGF）的作用不明确、剂量或给药途径不理想以及无法监测患者的基因转移。为了使该领域向前发展，需要解决的紧迫问题是：（i）找到合适的载体来克服物理障碍，（ii）开发一种新的方法来验证体内基因表达，（iii）剖析分子基因治疗的机制，以及（iv）在转化模型中证明安全性和有效性。 R01提案的意义在于验证化学缀合可用于显着提高质粒DNA的转染效率，新颖的分子成像平台将使我们能够监测活体受试者中基因治疗的药代动力学和生物分布，这是一种“智能”技术。载体系统”可以被设计为组织特异性和缺氧响应性，最终该基因治疗可以在未来用于小动物、大型动物和人类受试者。