Molecular Imaging of Targeted Cardiac Gene Therapy

心脏靶向基因治疗的分子影像

• 批准号: 7646002
• 负责人: Joseph C. Wu
• 金额: $ 41.04万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7646002
• 关键词: Address; Adenovirus Vector; Adenoviruses; Adverse effects; Animal Model; Animals; Apoptosis; Area; Arts; 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; Randomized Controlled Clinical Trials; Recruitment Activity; Reporter Genes; Research; Research Personnel; Response Elements; Rodent; Role; Route; Safety; Side; Stem cells; Switch Genes; System; Techniques; Testing; 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; public health relevance; sound; therapeutic angiogenesis; therapeutic gene; therapeutic target; transgene expression; vector; Address; Adenovirus Vector; Adenoviruses; Adverse effects; Animal Model; Animals; Apoptosis; Area; Arts; 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; Randomized Controlled Clinical Trials; Recruitment Activity; Reporter Genes; Research; Research Personnel; Response Elements; Rodent; Role; Route; Safety; Side; Stem cells; Switch Genes; System; Techniques; Testing; 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; public health relevance; 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）：大型II/III期临床试验的最新结果是腺病毒介导的VEGF输送的结果，即使到目前为止还没有令人失望的话，这是尚无定论。我们认为，一种更强劲的策略可能是利用HIF-11上游转录调节剂，该调节剂可以激活几个下游基因，例如VEGF，FGF，IGF，IGF，Angiopoietin和Erythropoietin。然而，由于羟基羟化酶2（PHD2）内源性降解，HIF-11的生物半衰期短。因此，我们假设对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，持久性和不受管制的血管生成可以导致心脏血管瘤，从而以靶向和调节方式控制基因表达。另一个优先事项是开发可用于非侵入性，纵向和定量的生存受试者中基因表达的新型技术。因此，该R01提案的主要目标是在向量设计，分子成像，血管生物学和翻译模型中使用我们的多学科专业知识来解决上述问题。我们的具体目的是（1）开发具有稳健和延长的转基因表达的智能矢量，（2）监测我们体内新型载体的药代动力学和生物分布，（3）证明了SHPHD2介导的基因治疗的机制，用于心肌缺失的基因疗法，以及（4）评估安全性，EFFICACESACY和OPTIVE SAIFETACY CORVERATION CORVETICALICE和TRENSITAL模型。在5年结束时，我们希望通过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。公共卫生相关性：尽管心肌缺血患者的初始第1阶段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）仅带来适度的好处。这些不一致归因于缺乏理想的递送载体，诸如VEGF之类的单个治疗基因的作用不清楚，次优剂量或给药途径以及无法监测患者的基因转移。为了使该领域向前迈进，需要解决的紧迫问题是：（i）找到合适的向量来克服物理障碍，（ii）开发一种新颖的方法，意味着验证体内基因表达，（iii）剖析基因疗法的分子机制，以及（iv）（iv）在移植模型中表现出安全性和效率。该R01提议的重要性是验证化学结合可以显着提高质粒DNA的转染效率，该新型分子成像平台将使我们能够监视基因治疗的药代动力学和基因疗法在生命受试者中的生物分配，以使“智能载体系统”旨在使用“智能媒介系统”，并且是跨越的动物，并且是基因的特定动物，并最终是替代的，并最终是良性的，并最终是该疾病的特定动物，并最终是该疾病的疾病，并最终是该动物的疾病。未来的人类受试者。