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.
Review Summary:
EXECUTIVE SUMMARY
The goal of this proposal is to examine mechanisms of cellular aging, or senescence, in the heart and as the basis for interventions that might slow or reverse this process. The applicant presents preliminary data from genetic mouse models suggesting that the enzyme Pim-1 promotes cardiac progenitor cell (CPC) proliferation and survival while antagonizing senescence. The applicant proposes to extend this work in three Specific Aims. In Aim 1, the applicant proposes to use engineered Pim-1 constructs to further define Pim-1’s role in antagonizing senescence in cultured CPCs. In Aim 2, the applicant proposes to generate and characterize human CPC lines expressing Pim-1 and also examine Pim-1’s role in different subcellular compartments. In Aim 3, the applicant proposes to explore the contribution of Pim-1 to CPC-mediated heart repair using murine models of myocardial infarction.
Reviewers agreed that this proposal addresses a major unsolved problem in the field of regenerative medicine. However, they questioned its responsiveness to the Basic Biology II Request for Applications (RFA), which is limited to studies utilizing human cells, except for groundbreaking reprogramming studies. While the applicant states at the beginning that human CPCs will be used throughout the project, it is unclear from the experimental descriptions which experiments are with mouse cells and which are with human. The only unambiguous declaration of human CPC use in the research plan is in Part 1 of Aim 2. Aim 3 describes work entirely in genetic mouse models. Reviewers also cautioned that the very existence of CPCs in the adult mammalian heart is a subject of debate in the field. While a collaborator’s letter assures the supply of human heart tissues, it was somewhat unclear whether these would comprise both young and senescent CPCs, and to what extent this might influence their use. Reviewers felt that, without some preliminary characterization of human CPCs, this proposal is premature with respect to this RFA.
Reviewers praised the wealth of preliminary data in this proposal, but pointed out that all of the presented data are on mouse cells, except for a statement in the supplemental data that human cardiac progenitor cells have been isolated and cultured. Furthermore, reviewers raised several concerns about the feasibility of the research plan. They noted that the in vivo studies utilize a single marker to identify CPCs, which may not be sufficient, given the lack of consensus in the field as to the precise identity of these cells. Reviewers would have also appreciated more detail regarding the isolation and characterization of CPC populations. At least one felt the preliminary data would have been more meaningful if statistical significance had been provided for the telomere length and stress studies. Others were concerned that the proposal focuses on a single pathway, when it is likely that parallel or convergent pathways might also contribute significantly to senescence in the heart. In general, reviewers were intrigued by the notion that cellular senescence compromises cardiac function, but many did not feel that this premise has been fully substantiated. These concerns may have been assuaged if stronger evidence were provided to demonstrate a clear correlation between Pim-1 expression in CPCs, cellular senescence, and functional loss in the heart.
Reviewers described the applicant as a well-established investigator with an outstanding publication record in the field of cardiac progenitors, repair and regeneration. They had no doubts that the assembled research team is well qualified to perform the proposed studies.
Overall, while reviewers appreciated that this proposal addresses a significant problem, the emphasis on murine studies as well as a lack of preliminary data from human cells undermined its feasibility and called into question its responsiveness to the RFA.
