Antagonizing aging and senescence of myocardial stem cells with Pim-1 kinase

Funding Type: 
Basic Biology II
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

In the last several decades, average lifespan has increased significantly. More individuals reach 85-90 years of age but often suffer from health related problems with severe limitations in functional activity, underscoring the need to improve the health and quality of life of this patient population. An additional critical question is whether the current limit in life expectancy actually reflects the ineluctable genetic clock or the increased incidence of congestive heart failure (CHF) with aging has interfered with the programmed death of the organ and organism, negatively influencing quality of life and maximum lifespan in humans. Morbidity and mortality for CHF continue to increase and parallel the extension in median lifespan of the population, pointing to aging as the major risk factor of the human disease. Recent data published from the American Heart Association document that there are 5.7 million patients affected by this disease in the United States alone with an incidence of 670,000 new cases per year. Importantly, the overwhelming majority of individuals with CHF are 65 years of age or older. The aging heart typically shows a decreased functional reserve and limited capacity to adapt to abrupt changes in hemodynamic load. But the critical question is whether the senescent heart is the product of aging-associated events or the result of a primary aging effect on the number and function of cardiac progenitor cells (CPC). A recent study strengthened the notion that myocyte replacement occurs in the human heart at a rate higher in young adults than in individuals at 75 years of age. CPCs and myocytes undergo replicative senescence with severe telomere shortening and expression of proteins typically found in old cells. These molecular modifications dictate irreversible growth arrest and cell death activation. Senescent CPCs and poorly contracting markedly hypertrophied myocytes accumulate, the pool of functionally competent CPCs is reduced, and cardiac decompensation supervenes defining the senescent heart phenotype. Although myocardial aging and heart failure may not necessarily deplete myocardial CPCs, strategies capable of interfering with telomere attrition, cellular senescence and death have three important objectives: a) Preventing and/or delaying the exhaustion of the CPC compartment; b) Enhancing the viability, engraftment and growth of the delivered cells within the tissue; and c) Increasing the efficiency of CPCs which, in turn, reduces dramatically the number of cells to be administered and, therefore, the time between cell isolation/expansion and treatment. Thus, the long-term objective is to identify whether genetic engineering of CPC with survival and proliferative signals promotes a youthful cardiac phenotype characterized by increased myocyte regeneration and preservation / expansion of the CPC pool.

Statement of Benefit to California: 

In 2004, the total healthcare cost in the US was1.9 trillion dollars and cardiovascular disease ranked as the most costly disease category, accounting for 8.3% of these overall costs. Cardiovascular disease and, in particular, myocardial infarction resulting in congestive heart failure, continues to be the number one cause of death in the US, killing some 300,000 Americans each year. Congestive heart failure is also the leading cause of hospital admissions. There are nearly 5 million Americans who are suffering from this illness, with 550,000 new cases reported annually. Despite recent advances in drug therapies for acute myocardial infarction, the average five-year survival for patients suffering this condition remains only at roughly 50% level. While cardiac transplantation is a well-established treatment for end-stage congestive heart failure, this treatment is limited to only 2,000 patients per year due to a severe and chronic shortage of acceptable donor hearts. As the most populous state, California bears the greatest public health impact of myocardial infarction and congestive heart failure as well, a burden that is only getting heavier as the population ages. There is a clear need for novel therapies for these disease conditions, the development of which will benefit California tremendously, from its population to the state’s public health system and its foundation in biomedical research. One such cutting edge treatment uses the genetic engineering technology which has already been shown to much promise in relevant animal models and is on track for translational implementation in the clinical setting.

In addition to the cost saving benefits that will be realized by the California healthcare system as a result of the development of this technology, there will also be significant economic development benefits realized by the State. All the funds will be reinvested in California, fueling economic growth and recovery in addition to furthering a likely revolutionary treatment of heart failure. This funding will also serve to create new jobs associated with the development of genetic modification of progenitor cells to enhance their regenerative capacity. Synergy can result as other cell therapies using related technologies and targeting different disease areas are likely to develop as a direct consequence of this funding, assuming a positive outcome for the current project. These funds will also directly support education and jobs at {REDACTED}, which are undergoing significant and painful budget reductions and losing critical talent.