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Regenerating Cardiac Cells With modRNA – An Interview With Dr. Lior Zangi

By Erica Arnold

Myocardial Infarction and Cell Regeneration Through modRNA

Myocardial infarction, also known as a heart attack, occurs when blood flow to the heart is restricted. Consequently, the heart muscle is damaged due to an inadequate supply of oxygen. When this occurs, billions of cardiomyocytes are killed, but only few can be regenerated. The loss of these cells leads to less efficient cardiac function and a higher mortality rate. Heart attack, and heart disease in general, has become a serious health problem world wide, particularly in the United States.

The severity of this disease has inspired scientist Dr. Lior Zangi of Harvard Medical School to conduct an experiment. He modified the mRNA (modRNA) for the VGEF-A (vascular endothelial growth protein) see if such modifications could improve cell regeneration after cardiac injury. This modRNA is altered by just a few nucleotides, enough so that it can no longer be recognized by endosomes, but can still translate functional proteins.

When VGEF-A modRNA was injected into a mouse model post myocardial infarction, a “pulse-like” expression of the VEGF-A protein was observed. This resulted in the migration of cardiac progenitor cells into the myocardium. The migration of progenitors significantly increased cardiac regeneration. Injection of modRNA also caused greater capillary density and a reduction of cell injury and death. Compared to control mice with an average survival rate of 60% after 1 month, experimental animals showed an average survival rate of 80%.

After this experiment, Dr. Zangi and his team tested the differentiation of WT1+ epicardial progenitors into endothelial cells. WT1+ epicardial progenitors are the major stem cells found in the adult heart. As shown earlier, a greater number of epicardial progenitors increases the efficiency of regeneration. In order to see how well the VEGF-A modRNA induced proliferation and differentiation of WT1+ progenitors, the cells were marked with WT1 CreERT2/+. Using this method, cell lineage could be tracked, and descendants of WT1+ progenitors could be identified.

Dr. Zangi, the lead scientist for these experiments, sat down with me and told me of his inspirations, scientific background, and his ideas for the future of his scientific career. Before earning his PhD, Zangi was a sniper in the Israeli Special Forces. With an interest in science and medicine, he went on to get his PhD in Immunology and subsequently acquired a position at Harvard Medical School.

Dr. Zangi decided that he wanted to research the effects of modRNA because he was interested in its effects on all organs of the body. He narrowed his research to the heart because he wanted to be able to combat heart disease. As he was completing this 3 ½ year experiment, Dr. Zangi says that he was very pleased with his results and believes that there are two new major findings. The idea that one single injection can lead something to repair itself fascinated him as well as the idea that even short, “pulse-like” delivery can create regeneration.

As for his future, Dr. Zangi plans to go on and study other progenitors and see what affect they can have on regeneration. He also plans to collaborate with researchers at MIT, who are using modRNA to attack cancer cells. In addition, AstraZeneca, a leading pharmaceutical company, are repeating Dr. Zangi’s experiment and hopefully, they can build upon it. He believes that there is a promising future for this field as they begin to focus more on stem cells and VEGF-A activation.

Overall, this study was successful in using VEGF-A modRNA to promote delivery of progenitors into the myocardium post myocardial infarction. However, more research is necessary to support the conclusion that VEGF-A modRNA stimulates cardiac regeneration. Clearly, this study and the work of Dr. Lior Zangi foreshadows an exciting future for this scientific field.

Zangi, Lior. et al. Modified mRNA Directs the Fate of Heart Progenitor Cells and Induces Vascular Regeneration after Myocardial Infarction. Nature 31.10 (2013): 898-907. Nature. 2013. Web. 2103.

http://www.nature.com/nbt/journal/v31/n10/full/nbt.2682.html#author-information

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