mRNA-Based Protein Replacement Therapy for the Heart

Abstract

Myocardial infarction (MI) and heart failure (HF) are the leading causes of death in the United States and in most other industrialized nations. MI leads to a massive loss of cardiomyocytes (CMs), which are replaced with non-CM cells, leading to scarring and, in most cases, HF. The adult mammalian heart has a low intrinsic regenerative capacity, mainly because of cell-cycle arrest in CMs. No effective treatment promoting heart regeneration is currently available. Recent efforts to use DNA-based or viral gene therapy approaches to induce cardiac regeneration post-MI or in HF conditions have encountered major challenges, mostly because of the poor and uncontrolled delivery of the introduced genes. Modified mRNA (modRNA) is a safe, non-immunogenic, efficient, transient, local, and controlled nucleic acid delivery system that can overcome the obstacles to DNA-based or viral approaches for cardiac gene delivery. We here review the use of modRNA in cardiac therapy, to induce cardioprotection and vascular or cardiac regeneration after MI. We discuss the current challenges in modRNA-based cardiac treatment, which will need to be overcome for the application of such treatment to ischemic heart disease.

Keywords: cardiac regeneration; gene therapy; mRNA therapy.

Figure 1

Methods of Gene Delivery to the Heart In vivo gene expression profiles for various methods of gene delivery to the heart. (A) Recombinant protein. (B) Modified mRNA (modRNA). (C) Adeno-associated viruses (AAVs).

Figure 2

Comparing Uptake of RNA and modRNA by the Cell (Left) modRNA delivery does not cause any activation of immune response and escapes RNase degradation. (Right) mRNA triggers activation of TLR7/8 and is prone to degradation by RNase.

Figure 3

Use of Modified mRNA Therapy in Prevention of Cardiac Remodeling modRNA can be used to improve the condition of ischemic injury by inducing cardiac and cardiovascular regeneration and cardiac proliferation.