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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

基本信息

批准号：
9982121
负责人：
YOUNG-WOOK WON
金额：
$ 50.7万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982121
关键词：
Acute myocardial infarction Affect Affinity Animal Model Base Pairing Binding Bone Marrow Stem Cell 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 cardiac repair cost effective cost effectiveness divalent metal driving force effective therapy gene therapy heart damage heart function improved intercalation interest migration nanomolar new technology novel preclinical trial protein aminoacid sequence recruit repaired response targeted delivery therapeutic gene

项目摘要

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