hESC mitochondrial transfer to empower withered cardiomyocytes

Funding Type: 
SEED Grant
Grant Number: 
RS1-00425
Investigator: 
ICOC Funds Committed: 
$0
oldStatus: 
Closed
Public Abstract: 
Heart failure is the most important cardiovascular health problem worldwide. It is a common end result of multiple diseases such as hypertension, coronary artery disease, diabetes and obesity. In the United States alone, it afflicts 5 million patients and a substantially larger number of asymptomatic subjects have an evidence of left ventricular dysfunction. In addition, as discussed above, at least 60-70 million people suffer from diseases that render them susceptible to development of HF. The disease imposes an economic burden of more than 25 billion dollars every year. The clinical syndrome of heart failure is characterized by relentless progression of disease and in spite of significant medical advances the prognosis of advanced HF has not improved. Before this cardiovascular scourge evolves into an epidemic, we need to start a two-pronged strategy; identify predisposed early to prevent the progression of disease, and develop newer methodology to salvage the failing myocardium. Newer strategies for empowering failing myocardium include human embryonic stem cells (hESC) injections in the heart muscle so that these cells could proliferate to assume the characteristics of heart muscle cells. However, we propose that we should move away from the orthodox attempts of transforming hESC to heart muscle before they are seeded into the myocyte-deficient regions. Instead, we would focus primarily on revitalizing withered heart muscle cells. In heart failure, the inexorable decline of LV function, of many pathogenetic mechanisms, has been attributed to an interrupted suicidal process (called apoptosis). During this process, the power houses of the muscle (called mitochondria) are depleted of intermediates involved in energy production. Hence heart failure is considered energy-deficient state. We propose that revitalization of mitochondria is necessary to provide energy to failing heart muscle cells and that HESC can be used as the source of new mitochondria. Such mitochondrial transfer to failing cells may result in partial alleviation of heart failure. We propose that preparation of extra-nuclear part of human embryonic stem (hES) cells and its delivery to withered myocytes will replenish these cells. The hybrid cells thus will be formed in the heart muscle with new mitochondria from the stem cells.
Statement of Benefit to California: 
Heart failure is the most important cardiovascular health problem worldwide. Various cardiovascular diseases such as hypertension, coronary artery disease, diabetes and obesity, eventually lead to heart failure. Approximately 5 million patients suffer from heart failure in US alone and a substantially larger number of asymptomatic subjects have an evidence of left ventricular dysfunction. In addition, as discussed above, at least 60-70 million people suffer from diseases that render them susceptible to development of HF. The disease imposes an economic burden of more than 25 billion dollars every year. California has the lowest death adjusted death rate for heart failure compared to other states but yet carries one of the largest heart failure loads in the country (based on the ICD-9; 428.0-428.9). The clinical syndrome of heart failure is characterized by relentless progression of disease and in spite of significant medical advances the prognosis of advanced HF has not improved. We need to develop newer methodology to salvage the failing myocardium. Recently some revolutionary newer strategies have been proposed for empowering failing myocardium such as myocardial injection of human embryonic stem cells (hESC) so that these cells could proliferate to assume the characteristics of heart muscle cells. However, we propose that we should move away from the orthodox attempts of transforming hESC to heart muscle before they are seeded. Instead, we would focus primarily on revitalizing withered heart muscle cells, by mere mitochondrial transfer from the stem cells. California is the pioneering state that allows the jusdicious use of embryonic stem cells for research. This project promises not only the new hope for heart failure but may also allow a new paradigm in the management of various chronic degenerative diseases wherein energy production is limited. It is expected that if the proof of principle is demonstrated by the proposed experiment, such a technology would be immediately translated into the clinical experiment. Use of embryonic stem cells without the nucleus would preclude the potential devastating malignant transformations. Management of chronic debilitating diseases with virtually no side effects would result in quantitative and qualitative improvement in health. This should also offer an improvement in effective manpower within the state.

© 2013 California Institute for Regenerative Medicine