A combination of three genes has been found to have the ability to reprogram cells in the scars caused by heart attacks into functioning muscle cells, and the addition of a gene that triggers the growth of blood vessels enhances that effect.

“The idea of reprogramming scar tissue in the heart into functioning heart muscle was exciting,” said Dr. Todd K. Rosengart, chair of the Michael E. DeBakey department of surgery at Stony Brook University Medical Center (BCM; http://stonybrookmedicine.edu) and the report’s corresponding author. “The theory is that if you have a big heart attack, your doctor can just inject these three genes into the scar tissue during surgery and change it back into heart muscle. However, in these animal studies, we found that even the effect is enhanced when combined with the VEGF [the vascular endothelial growth factor] gene.”

“This experiment is a proof of principle,” said Dr. Ronald G. Crystal, chairman and professor of genetic medicine at Weill Cornell Medical College (New York, NY, USA) and an innovator of gene therapy, who played an important role in the research. “Now we need to go further to understand the activity of these genes and determine if they are effective in even larger hearts.”

Blood supply is blocked off to the heart during a myocardial infarction, which results in the death of heart muscle. The damage leaves behind a scar and a weakened heart. Ultimately, most individuals who have had serious heart attacks will develop heart failure.

Changing the scar tissue into heart muscle would strengthen the heart. To achieve this, during surgery, Dr. Rosengart and his colleagues transferred three forms of the VEGF gene that enhances blood vessel growth or an inactive material (both attached to a gene vector) into the hearts of rats. Three weeks later, the rats received either Gata4, Mef 2c, and Tbx5 (the combination of transcription factor genes called GMT) or an inactive material.

The GMT genes alone reduced the amount of scar tissue by half compared to animals that did not receive the genes, and there were more heart muscle cells in the animals that were treated with GMT. The hearts of animals that received GMT alone also worked better as defined by ejection fraction than those who had not received genes.

The hearts of the animals that had received both the GMT and the VEGF gene transfers had an ejection fraction four times greater than that of the animals that had received only the GMT transfer. Dr. Rosengart stressed that more research needs to be done to validate that the effect of the VEGF is real, but it has real potential as part of a new treatment for heart attack that would minimize heart damage. “We have shown both that GMT can effect change that enhances the activity of the heart and that the VEGF gene is effective in improving heart function even more,” said Dr. Crystal.

The project started with the idea of induced pluripotent stem cells—reprograming mature specialized cells into stem cells that are immature and can differentiate into different specific cells needed in the body. Dr. Shinya Yamanaka and Sir John B. Gurdon received the Nobel Prize in Medicine and Physiology for their work toward this goal this year.

However, use of induced pluripotent stem cells has the potential to cause tumors. To avoid this, researchers used the GMT cocktail to reprogram the scar cells into cardiomyocytes in the living animals. Dr. Rosengart and his colleagues are now going a step farther—stimulating the generation of new blood vessels to provide circulation to the new cells.

Related Links:
Stony Brook University Medical Center
Weill Cornell Medical College