Modified mRNA as a therapeutic tool to induce cardiac regeneration in ischemic heart disease

Abstract

Ischemic heart disease (IHD) is a leading cause of morbidity and mortality in developed countries. Current pharmacological and interventional therapies provide significant improvement in the life quality of patient; however, they are mostly symptom-oriented and not curative. A high disease and economic burden of IHD requires the search for new therapeutic strategies to significantly improve patients' prognosis and quality of life. One of the main challenges during IHD is the massive loss of cardiomyocytes that possess minimal regenerative capacity. Recent understanding of the pathophysiological mechanisms underlying IHD, as well as new therapeutic approaches provide new hope for patients suffering from IHD. Synthetic modified mRNA (modRNA) is a new gene delivery vector that is increasingly used in in vivo applications. modRNA is a relatively stable, non-immunogenic, highly-expressed molecule that has been shown to mediate high and transient expression of proteins in different type of cells and tissues including cardiomyocytes. modRNA properties, together with its expression kinetics in the heart make it an attractive option for the treatment of IHD, especially after myocardial infarction. In this review we discuss the role of gene therapy in cardiac regeneration as an approach to treat IHD; traditional and innovative gene delivery methods; and focus specifically on modRNA structure, mode of delivery, and its use for the induction of endogenous regenerative capacity, mainly in the context of IHD. WIREs Syst Biol Med 2017, 9:e1367. doi: 10.1002/wsbm.1367 For further resources related to this article, please visit the WIREs website.

FIGURE 1

Ideal treatment for ischemic heart disease. Gene therapy goals in treating of IHD are in prevention of pathological heart remodeling by: (a) activation of adult cardiomyocytes proliferation (b) attenuating the innate and adaptive immune response (c) induction of angiogenesis (d) preventing cardiac cells apoptosis and necrosis.

FIGURE 2

Possible modification of mRNA structure and delivery vehicle for optimal gene expression in the heart. Stability and expression level of proteins can be optimize by modifying the mRNA composition and structure. The modRNA can be delved naked or after complexing it with biomaterials to achieve optimal stability and penetration to the cardiac cells.

FIGURE 3

Routes of modRNA delivery to the myocardium. A current diagram of existing cardiac gene delivery techniques considers site and method of administration and, interventional approach. Methods for direct gene delivery include injection from epicardial or endocardial layers into myocardium. A global transduction of the myocardium can only be achieved with intravascular transfer, which includes simple intravenous injection, intracavitary administration and intracoronary arteries route of infusion.

FIGURE 4

Main phases of Post-MI myocardial remodeling in mouse. modRNA expression occurs during inflammatory and proliferative phases, when most of the changes in cardiac function take place.