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.
/ RELEVANCE TO PUBLIC HEALTH A significant barrier to the convenience administration of therapeutic genes to repair damaged hearts is the inability to specifically deliver the gene of interest to the infarct region of the heart upon systemic injection. We intend to develop a non-invasive targeted systemic strategy to deliver a therapeutic gene to the damaged heart of patients with chronic heart failure.
| Lee, Daniel Y; Lim, Kwang Suk; Valencia, Gabriel M et al. (2018) One-Step Method for Instant Generation of Advanced Allogeneic NK Cells. Adv Sci (Weinh) 5:1800447 |
