492. Bioreducible Dendrimer Polymer-Mediated Human Relaxin Expression for Post-Infarct Cardiac Remodeling
Authors: Young Sook Lee, Jaesung Kim, Kihoon Nam, Il-Kyu Choi, Jung-Eun Oh, Chae-Ok Yun, Sung Wan Kim
Journal: Molecular Therapy (2015)

After myocardial infarction (MI), the heart undergoes a series of structural changes, termed post-infarct cardiac remodeling, at the organ, cellular, and molecular levels. During decades, diverse efforts in experimental and clinical trials have been made to investigate promising cardio-protective strategies. In our previous work, the aggressive rescue for the central fibrotic lesion in left ventricle (LV) after MI is emerging as one of key therapeutic targets to overcome limited functional and prognostic improvements. Recently, diverse potent cardio-protective effects of RLX render it one of the most likely candidates for the elusive physiological shield against cardiovascular disease, including MI. Here, we developed a bioreducible arginine-grafted bioreducible poly(CBA-DAH) (ABP) polymer and dendrimer type PAM-ABP polymer, retaining the unique properties of reductive disulfide linkers coupled with the advantage of arginine residues to enhance cell penetration and exhibiting long-term retention in the ECM giving a very high local concentration of the carried substrate and acting as a drug depot at the cellular surface. We hypothesized that intramyocardial delivery of anti-fibrotic human relaxin plasmid DNA (phRLX) by a dendrimer type PAM-ABP polymer after MI would exhibit high affinity for the cardiac ECM and preserve cardiac geometry and systolic function. These results of human RLX gene therapy delivered by a bioreducible PAM-ABP polymer would provide insight into reconstruction of post-infarct cardiac remodeling focused on cardiac ECM. We constructed the plasmids (HR1) expressing human relaxin protein 1 (R1) with hypoxia response element (HRE) 12 copies. HR1 gene delivered by bioreducible PAM-ABP polymer showed significant dose-dependent functional improvement on both early and sustained time points in rats. The 100 µg HR1/PAM-ABP conserved significantly improved LV systolic function 1 wk and 3 wks after MI than ischemia-reperfusion (I-R) and other treatment groups. The resolution of regional wall motional abnormalities and the increase of coronary blood flow supported functional improvements of HR1/PAM-ABP. However, the 50 μg HR1/PAM-ABP group showed improved systolic function 3 wks after MI, comparable level to the sham thoracotomy group. At 4 wks after MI in rat hearts, I-R, PEI polyplex, and HR1 plasmid-alone groups showed remarkable accumulations in cardiac ECM composition, such as collagen I, III, fibronectin, and elastin. However, the 100 μg and 200 μg HR1/PAM-ABP polyplex showed favorable post-infarct cardiac ECM remodeling reflected on the protected cardiac ECM compositions, up to the control level of thoracotomy group. The study presented a new paradigm for the design of a smart combinational polyplex that reverses adverse post-infarct cardiac remodeling with a therapeutic gene that exhibits potent antifibrotic effects and a carrier that exhibits high affinity and retention in the cardiac ECM.