Direct Cardiac Reprogramming for Heart Regeneration

Heart disease is a leading cause of mortality. The underlying pathology is typically loss of heart muscle cells that leads to heart failure. Because heart muscle has little or no regenerative capacity after birth, current therapeutic approaches are limited for the over 5 million Americans who suffer from heart failure. Our recent findings regarding direct reprogramming of a type of structural cell of the heart, called fibroblasts, into cardiac muscle-like cells using just three genes offers a novel approach to achieving cardiac regeneration. 50% of cells in the human heart are cardiac fibroblasts, providing a potential source of new heart muscle cells for regenerative therapy. We simulated a heart attack in mice by blocking the coronary artery, and have been able to reprogram existing mouse cardiac fibroblasts into new muscle by delivering the three genes into the heart. We found a significant reduction in scar size and an improvement in cardiac function that persists after injury. The reprogramming of cells in the intact organ was more complete than in cells in a dish. We now identified a combination of factors that reprogram human and pig cardiac fibroblasts and are optimizing a gene therapy approach to introduce cardiac reprogramming genes into the heart of pigs. In a pig model of cardiac injury, these factors were able to convert non-muscle cells into new muscle in the area of injury. We also found a viral vector that can preferentially infect the fibroblasts compare to the muscle cells. We are now in a position to test for functional improvement in pigs.

Heart disease is a leading cause of mortality. The underlying pathology is typically loss of heart muscle cells that leads to heart failure. Because heart muscle has little or no regenerative capacity after birth, current therapeutic approaches are limited for the over 5 million Americans who suffer from heart failure. Our recent findings regarding direct reprogramming of a type of structural cell of the heart, called fibroblasts, into cardiac muscle-like cells using just three genes offers a novel approach to achieving cardiac regeneration. We simulated a heart attack in mice by blocking the coronary artery, and have regenerated damaged hearts by converting existing mouse cardiac fibroblasts into new muscle by delivering the three genes into the heart. We have found that a combination of the three genes used in mice plus two additional factors were sufficient to identified to reprogram human and pig cardiac fibroblasts and are optimizing a gene therapy approach to introduce cardiac reprogramming genes into the heart of pigs. In a pig model of cardiac injury, we identified the optimal combination of factors that was able to convert non-muscle cells into new muscle in the area of injury. We have completed a pilot study of these five factors for functional improvement using MRI to measure cardiac output 3 days after injury and 2 months after treatment with the reprogramming factors. We also found a viral vector that can preferentially infect the fibroblasts compare to the muscle cells and have confirmed this activity. We are now testing for functional improvement in pigs using various viral vectors.

Heart disease is a leading cause of mortality. The underlying pathology is typically loss of heart muscle cells that leads to heart failure. Because heart muscle has little or no regenerative capacity after birth, current therapeutic approaches are limited for the over 5 million Americans who suffer from heart failure. Our recent findings regarding direct reprogramming of a type of structural cell of the heart, called fibroblasts, into cardiac muscle-like cells using just three genes offers a novel approach to achieving cardiac regeneration. 50% of cells in the human heart are cardiac fibroblasts, providing a potential source of new heart muscle cells for regenerative therapy. We simulated a heart attack in mice by blocking the coronary artery, and have been able to reprogram existing mouse cardiac fibroblasts in to new muscle by delivering the three genes into the heart. We found a significant reduction in scar size and an improvement in cardiac function that persists after injury. The reprogramming of cells in the intact organ was more complete than in cells in a dish. We now propose to develop the optimal gene therapy approach to introduce cardiac reprogramming genes into the heart, to establish the optimal delivery approach to administer virus encoding cardiac reprogramming factors that results in improvement in cardiac function in a pig model of cardiac injury, and to establish the safety profile of in vivo cardiac reprogramming in a pig model.

Heart disease is a leading cause of mortality. Because heart muscle has little or no regenerative capacity after birth, current therapeutic approaches are limited for the over 5 million Americans who suffer from heart failure. Our recent findings regarding direct reprogramming of a type of structural cell of the heart, called fibroblasts, into cardiac muscle-like cells using just three genes offers a novel approach to achieving cardiac regeneration. In the last reporting period we have tested this approach in large animals (pigs) and seen an improvement in cardiac function after cardiac injury with the therapeutic approach. We also developed a chemical means for enhancing the efficiency and speed of reprogramming cells and shown that this results in 5-fold more new heart muscle in mice. Finally, we have developed a new viral vector with which to deliver the therapeutic project in human and pigs and shown that this vector can convert human cells efficiently. We are now close to finalizing a therapeutic product that could be packaged in the viral vector.