Myocardial infarction (MI)—also known as a heart attack—is a leading cause of sickness and death, world-wide. Due to massive loss of heart muscle cells, and the inability of the heart to regenerate, the heart is left with a permanent fibrotic scar. This scar, and the expansion of the scar to uninjured heart tissue, leads to cardiac functional impairment and eventually heart failure. Therefore, the ultimate aim of this project is to use cardiac regenerative medicine to modulate damaging aspects of the scar or replace it with functional muscle cells.
By combining cell reprogramming technology with lipid nanoparticle (LNP) chemistry, this project will test a novel strategy to replace the scar tissue that forms after MI with heart muscle cells. To do this we will coax fibroblasts—the primary cell-type responsible for forming scar tissue—to transform into heart muscle cells. This can be achieved by promoting the expression of genes that are known as ‘cardiac transcription factors’: binding protein 4 (GATA4), myocyte enhancer factor 2C (MEF2C), and T-box transcription factor 5 (TBX5), (collectively termed ‘GMT’). Conversion of fibroblasts to muscle cells through GMT expression is well established. However, clinical translation of this technology to regenerate the heart has been limited by a lack of methods to safely deliver the genetic material that enables GMT expression in the heart after MI.
To overcome this limitation, in this project, we will test whether GMT genetic material can be delivered by mRNA-loaded LNPs (mRNA-LNPs). The feasibility of this has been recently demonstrated by us and others, showing mRNA-LNPs can be used to genetically alter fibroblasts within scars after MI. But, no study to date has tested whether mRNA-LNPs can be used to induce GMT expression in cardiac scar tissue and convert this scar to working muscle. We will test this.
If this proof-of-concept study is successful, its implications will be far-reaching, potentially transforming treatment for people who have suffered from MI, by preventing the onset of heart failure.
Last updated15 October 2025