A new miRNA delivery system in vivo for the treatment of myocardial infarction

2020-04-28

Myocardial infarction (MI) is closely related to coronary artery occlusion, which can lead to serious downstream myocardial cell death, is the main cause of inducing heart disease and stroke, and seriously threatens human health. MicroRNA (miRNA) can be used to effectively treat Mi related heart failure. However, how to efficiently and sustainably transfer miRNA to the heart muscle to achieve functional improvement and stimulate endogenous myocardial repair is the key problem of miRNA therapy. MiR-199a, for example, plays a role in promoting the division of cardiomyocytes, but the previously reported gene transfer method based on adeno-associated virus (AAV) has a risk of virus immune response. Therefore, the development of new relatively safe non-virus transfection methods has aroused extensive interest of researchers.

Recently, Dr. Yang Huaxiao of Stanford University cardiovascular research center and Li Kai, Associate Professor / researcher of Biomedical Engineering Department of South University of science and technology, established a new miRNA in vivo delivery system (microRNA Nanoparticle (miNP), which uses polymer nanoparticles to carry miRNA to local miRNA delivery in shear thinned injectable hydrogels, has high stability and low toxicity, and significantly improves miRNA transfection efficiency in stem cell derived cardiomyocytes and vascular endothelial cells. The in vivo delivery system of miRNA reported in this study has the following significant characteristics: 1) miRNA has a shelf life of up to half a year to one year, which can withstand repeated freezing and thawing, maintain stable particle size distribution and complete miRNA release; 2) miRNA significantly improves the transfection efficiency of miRNA in stem cell-derived cardiomyocytes and vascular endothelial cells by using membrane penetrating peptide. 3) With the excellent biocompatibility of polymer materials, the cytotoxicity of MINP was significantly lower than that of liposome rnaimax.

In order to effectively deliver miNP to the heart and control the release of miRNA into cardiomyocytes, Dr. Yang Huaxiao and Professor Li Kai, through cooperation with Professor Sarah Heilshorn of Standford School of materials, used injectable, biodegradable and highly biocompatible polypeptide hydrogels (ELP-HA) as carriers to successfully inject miNP into the infarcted part of the heart to solve this problem. Through animal experiments, they found that the MINP could stay in the heart for up to one month, and the ejection fraction (EF) of the treated group increased from 45% to 64%, and the infarct area was also reduced by half. What's more interesting is that a large amount of new vascular tissue was found in the border zone. In order to further verify the results of in vivo experiments, they used embryonic stem cells induced cardiomyocytes, vascular endothelial cells and primary human cardiac fibroblasts to conduct a large number of disease simulation experiments in vitro. The results showed that both in normoxic and anoxic environment, MINP could effectively stimulate the division and proliferation of cardiomyocytes and vascular endothelial cells, and the cell cycle also entered G1 / s and S / M phase, which could promote angiogenesis, and could not induce further fibroblast proliferation and tissue fibrosis.

At the same time, the giacca research group of the International Center for genetic engineering and biotechnology in Italy recently carried out large animal (pig) experiments. They found that miR-199a also had a very obvious regeneration effect in pigs. However, because the adenovirus transfection method could not repair the heart tissue in a controlled way, it caused a cardiac disorder and was lethal. Therefore, they finally suggested that although gene therapy can achieve significant cardiac regeneration, further optimization of administration mode and dosage can ultimately achieve cardiac regeneration based on gene therapy. The miRNA delivery system designed in this study based on polymer nanoparticles provides an efficient and safe gene therapy scheme for myocardial infarction, which has the potential to solve this problem It provides a basis for further clinical trials.

This research result was recently published on ACS Nano. Li Kai, associate professor of Biomedical Engineering Department of South University of science and technology, is the corresponding author. Yang Huaxiao, Ph.D., Stanford University, is the first author and co corresponding author.