Repairing the heart: State-of the art delivery strategies for biological therapeutics

Abstract

Myocardial infarction (MI) is one of the leading causes of mortality worldwide. It is caused by an acute imbalance between oxygen supply and demand in the myocardium, usually caused by an obstruction in the coronary arteries. The conventional therapy is based on the application of (a combination of) anti-thrombotics, reperfusion strategies to open the occluded artery, stents and bypass surgery. However, numerous patients cannot fully recover after these interventions. In this context, new therapeutic methods are explored. Three decades ago, the first biologicals were tested to improve cardiac regeneration. Angiogenic proteins gained popularity as potential therapeutics. This is not straightforward as proteins are delicate molecules that in order to have a reasonably long time of activity need to be stabilized and released in a controlled fashion requiring advanced delivery systems. To ensure long-term expression, DNA vectors-encoding for therapeutic proteins have been developed. Here, the nuclear membrane proved to be a formidable barrier for efficient expression. Moreover, the development of delivery systems that can ensure entry in the target cell, and also correct intracellular trafficking towards the nucleus are essential. The recent introduction of mRNA as a therapeutic entity has provided an attractive intermediate: prolonged but transient expression from a cytoplasmic site of action. However, protection of the sensitive mRNA and correct delivery within the cell remains a challenge. This review focuses on the application of synthetic delivery systems that target the myocardium to stimulate cardiac repair using proteins, DNA or RNA.

Keywords: Cardiac repair; Modified mRNAs; Nucleic acid delivery; Protein delivery; Synthetic delivery approach.