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.

Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

“…Protein replacement therapies based on IVT mRNA have been mainly directed to the liver [201], lungs [202], and heart [203] because of the accessibility of these organs. However, other organs and tissues, such as skin [204], back of the eye [205] or nasal cavity [131] have also been evaluated as target sites.…”

Practical Synthesis of Cap‐4 RNA

“…Our growing understanding of the functionality of 5′ caps and the consequences of disrupting cap‐dependent biochemical processes that result in severe medical disorders make 5′ caps attractive for the development of novel pharmaceutic and therapeutic approaches . Potential applications for cap analogues are foreseeable in antiviral therapy, cancer treatment (including eIF4E targeting and mRNA‐based immunotherapy), spinal muscular atrophy treatment, and treatment of genetic diseases by mRNA‐based protein replacement therapy . Essential for the success of RNA‐based therapeutics is the development of methods to introduce mRNA into cells and the improvement of stability and translation efficiency of the therapeutic RNA itself .…”

“…Potential applications for cap analogues are foreseeable in antiviral therapy, cancer treatment (including eIF4E targeting and mRNA‐based immunotherapy), spinal muscular atrophy treatment, and treatment of genetic diseases by mRNA‐based protein replacement therapy . Essential for the success of RNA‐based therapeutics is the development of methods to introduce mRNA into cells and the improvement of stability and translation efficiency of the therapeutic RNA itself . The high potential of mRNA‐cap‐based approaches has been demonstrated in the first application of 5′‐capped RNAs in preclinical studies …”

“…Essential for the success of RNA‐based therapeutics is the development of methods to introduce mRNA into cells and the improvement of stability and translation efficiency of the therapeutic RNA itself . The high potential of mRNA‐cap‐based approaches has been demonstrated in the first application of 5′‐capped RNAs in preclinical studies …”

In vitro-Transcribed mRNA Therapeutics: Out of the Shadows and Into the Spotlight

“…Introducing mRNA into the heart, however, has proven to be very challenging. Despite the difficulties, several preclinical studies have shown regeneration of cardiac tissue using a variety of IVT mRNA, as illustrated in the review by Magadum et al 6 Augmenting vascularization of the infarcted heart using mRNA is now under clinical evaluation. Another promising area of IVT mRNA application is in the field of monoclonal antibodies, which is now one of the fastest growing pharmaceutical sectors in the market.…”