Li Li

PI / Investigator: Li Li, St Vincent’s Institute of Medical Research, Melbourne, Australia (Mentor: Jarmon Lees)

Award Type: Graduate Research Fellowship co-funded with FARA US

Grant Title: Preclinical evaluation of novel targets for FRDA cardiomyopathy

Lay Summary: Heart disease is a leading cause of death in Friedreich ataxia, brought on by disease and dysfunction in all the different cells that make up the human heart. Unfortunately, there is currently no treatment to slow the progression of Friedreich ataxia heart disease, nor is there a cure.

Stem cells can develop into a wide variety of different types of cells. We have used stem cells from people with Friedreich ataxia in the lab to grow most of the different cell types found in the human heart including the beating heart cells (cardiomyocytes), vascular cells (endothelial cells and smooth muscle), and structural support cells (fibroblasts). We have recently used these cells to investigate the abnormalities in the Friedreich ataxia heart. When we compare them to cells grown from people without Friedreich ataxia, the Friedreich ataxia cardiac cells display clear differences. For example, the beating heart cells beat more slowly, and the vascular cells are less able to form viable blood vessels, providing clues to why the heart may not function as well in people with Friedreich ataxia. We have also used stem cells to grow 3D human heart tissue containing all these cell types. When Friedreich ataxia cells were used to engineer these human heart tissues, we found increased tissue death and impaired beating function compared to the control cells, similar to what is seen clinically in people with Friedreich ataxia.

To look deeper into the cell to find a reason for these differences, my lab has examined the levels of messenger RNA, the molecules that carry the active genetic instructions for the cell. By comparing which messenger RNAs are active in the Friedreich ataxia cells compared to the non-Friedreich ataxia cells, we found a number of very marked differences in all cardiac cell types. Excitingly, there were eight key RNAs that were significantly increased in the Friedreich ataxia cells. These RNAs have previously been shown to play important roles in cellular damage, vascular disease, and mitochondrial dysfunction, but have never been investigated in Friedreich ataxia heart disease or Friedreich ataxia in general.

The objective of my PhD is to examine the therapeutic potential of correcting the expression of these RNAs as a treatment for Friedreich ataxia heart disease. Specifically, I will determine if reducing the amount of each RNA in Friedreich ataxia cardiac cells can rescue the diseased changes we see in these cells. Then, using our 3D human heart tissue model, I will select the best performing candidates to determine if reducing their expression can protect the heart tissue from death and restore healthy beating function. And finally, I will assess the ability of the top two performing candidates to protect heart function in a mouse model of Friedreich ataxia heart disease. My PhD will establish novel therapeutic targets for Friedreich ataxia heart disease, a leading cause of death in people with Friedreich ataxia.