Targeted Systemic Delivery of SDF-1 DNA for the Treatment of Chronic Heart Disease

SDF-1 DNA 的靶向全身递送用于治疗慢性心脏病

• 批准号: 10220114
• 负责人: YOUNG-WOOK WON
• 金额: $ 47.15万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220114
• 关键词: Acute myocardial infarction; Affect; Affinity; Animal Model; Base Pairing; Binding; CXCR4 gene; Cardiac; Cardiac Myocytes; Cations; Cells; Charge; Chronic; Clinical Trials; Complex; Congestive Heart Failure; Cysteine; DNA; Devices; Dose; Engraftment; Evaluation; Genes; Genetic Materials; Goals; Heart; Heart Diseases; Homing; Hypoxia; Infarction; Injections; Ions; Lead; Left ventricular structure; Ligands; Mediation; Mesenchymal Stem Cells; Metals; Methods; Modeling; Modification; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nature; Patients; Peptides; Plasmids; Play; Public Health; Rattus; Recovery; Reporting; Role; Series; Site; Sulfhydryl Compounds; Technology; Therapeutic; Time; Transfection; Treatment Efficacy; base; bone marrow mesenchymal stem cell; cardiac repair; cost effective treatment; cost effectiveness; divalent metal; driving force; gene therapy; heart damage; heart function; improved; intercalation; interest; migration; nanomolar; new technology; normoxia; novel; preclinical trial; protein aminoacid sequence; recruit; repaired; response; targeted delivery; therapeutic gene

PROJECT SUMMARY / ABSTRACT Stromal-derived factor-1 (SDF-1)-based gene therapy that can improve mesenchymal stem cell (MSC) homing to the region of myocardial infarct for the treatment of acute myocardial infarction (MI) or chronic heart failure (CHF) has shown considerable promise in preclinical and clinical trials. However, the most established technology requires trans-endocardial injection using a specific device, which can only be handled by an expert. For convenience administration and cost-effective treatment, a targeted systemic delivery strategy has to be developed. In this application, a plasmid DNA encoding SDF-1 will be systemically and specifically delivered to the infarct site by the formation of the SDF-1/ischemic myocardium targeting peptide (IMTP) complex. To generate the SDF-1/IMTP complex, for the first time, we utilize the ligand-to-metal charge transfer transition allowing for direct incorporation of the targeting peptide to the plasmid SDF-1 DNA without the need for any gene carriers. We hypothesized that the LMCT transition between Zn2+ ions and the sulfhydryl group in cysteine of the targeting peptide could spontaneously drive the integration of the peptide to the plasmid SDF-1 that has already been modified to contain Zn2+ ions. It has been known that divalent metal ions, such as Zn2+, lead to the conversion of normal B-DNA to metal-bound DNA (M-DNA) through intercalation into the DNA base pairs in the pH range of 7.0-8.5. In the preliminary studies, we generated M-DNA using Zn2+ ions, confirmed the formation of the M-DNA/targeting peptide complex through the LMCT transition, and demonstrated that the M-DNA/targeting peptide complex led to the enhancement in the gene transfection in the target cells. In this project, in an animal model of CHF, we intend to demonstrate therapeutic efficacy of the targeted systemic delivery of a plasmid SDF-1 DNA by the formation of the SDF-1/IMTP complex generated through the LMCT transition. To achieve the final goal, we intend to demonstrate the followings: 1) direct integration of IMTP into the SDF-1 plasmid through the LMCT transition; 2) targeted transfection of the SDF-1 gene into hypoxic primary cardiomyocytes and the infarct site in the animal model; and 3) facilitated migration of MSCs towards the SDF-1 gradient in the animal model.

项目摘要 /摘要 基于基质的因子-1（SDF-1）基因疗法，可以改善间质干细胞（MSC）寄养 到治疗急性心肌梗塞（MI）或慢性心力衰竭的心肌梗塞区域 （CHF）在临床前和临床试验中表现出了巨大的希望。但是，最成熟的 技术需要使用特定设备的跨心膜注射，只能由 专家。为了方便管理和具有成本效益的治疗，有针对性的全身交付策略具有 要开发。在此应用中，编码SDF-1的质粒DNA将是系统，具体的 通过形成SDF-1/缺血性心肌靶向肽（IMTP），传递到梗塞部位 复杂的。为了生成SDF-1/IMTP复合物，我们首次使用配体电荷转移 过渡允许将靶肽直接掺入质粒SDF-1 DNA，而无需 对于任何基因载体。我们假设Zn2+离子与硫酸基团之间的LMCT转变 靶肽的半胱氨酸可以自发地驱动肽与质粒SDF-1的整合 已经对其进行了修改以包含Zn2+离子。众所周知，二价金属离子，例如Zn2+， 导致正常B-DNA通过插入DNA碱的转化为金属结合的DNA（M-DNA） pH范围为7.0-8.5的对。在初步研究中，我们使用Zn2+离子生成M-DNA，证实 通过LMCT转变形成M-DNA/靶向肽复合物，并证明了 M-DNA/靶向肽复合物导致靶细胞中基因转染的增强。在这个 项目，在CHF的动物模型中，我们打算证明目标全身性的治疗功效 通过通过LMCT产生的SDF-1/IMTP复合物的形成递送质粒SDF-1 DNA 过渡。为了实现最终目标，我们打算证明以下内容：1）将IMTP直接集成到 通过LMCT跃迁的SDF-1质粒； 2）将SDF-1基因靶向转染到低氧中 动物模型中的原发性心肌细胞和梗塞部位； 3）促进MSC迁移到 动物模型中的SDF-1梯度。