Heart Disease

Coding Dimension ID: 
295
Coding Dimension path name: 
Heart Disease
Funding Type: 
SEED Grant
Grant Number: 
RS1-00169
Investigator: 
ICOC Funds Committed: 
$714 654
Disease Focus: 
Heart Disease
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
This work is directly relevant to human embryonic stem cell (hESC) research because it brings new ideas about novel compounds to affect cardiomyogenesis. The work addresses an urgent need to develop new agents to treat cardiovascular disease. We will develop potent and selective drug-like molecules as cardiomyocyte differentiation agents. Heart disease is the leading cause of mortality and decline in the quality of life in the developed world. The ability of hESCs to form cardiomyocytes has spawned hope that these cells may be used to replace damaged myocardium. Despite their ability to form cardiomyocytes, efficient and controlled cardiomyogenesis in ESC cultures has not been achieved due to the unavailability of differentiation agents and an incomplete understanding of the pathways that regulate cardiac development. Success has been achieved in developing a robust and dependable high-throughput assay to study the effects of small molecules on cardiomyocyte differentiation. Powerful cell-based assays were developed and provided readouts that led to high-content results because multiple signals were probed. The assay is capable of capturing fast or long-acting biology because of the time-course readouts. Cell-based assays are superior to molecular screens because the cell-based assay delivers active compounds or “hits” that are permeable and non-cytotoxic. Moreover, refined “hits” can be used as probes to reveal novel signaling pathways and proteins that control differentiation, in a process termed chemical biology. By taking advantage of knowledge of the current “hits” we will rapidly synthesize novel drug-like compounds in a low-risk approach to. The “hits” will be refined and improved through an efficient synthetic process we use in our lab called “Dynamic Medicinal Chemistry”. Even after miniaturization and automation, screening is still expensive. A key to improve the screening process is to use pharmacologically active, drug-like compounds to provide rich target-relevant information. Intelligently designing libraries for screening by incorporating drug-like features into “lead” library design will improve the attrition rate and lead to more pharmacologically relevant compounds for future studies. This proposal is directly responsive to the California Institute for Regenerative Medicine SEED Grant Program because it provides for developing and testing new agents of use in cardiomyoenesis of hESCs. Importantly, it brings new investigators and a collaborative approach to the stem cell field. The agents discovered and developed may hold great promise as the groundwork for future medications development for a new class of damaged myocardium replacement agents. The theoretical rationale for the work is the use of high-content screening coupled with drug-like new agent discovery approaches. The work will also be of use in the elucidation of key biochemical targets and novel signaling pathways important in hESC cardiomyogenesis.
Statement of Benefit to California: 
In 2002, in the State of California, approximately 697,000 adult Californians died from heart disease. The cost as measured by loss of lifelong earnings was more than $79 billion. Setting aside the pain and suffering, the economic impact of cardiovascular disease to the State of California is staggering. Despite recent advances in cardiovascular medications development, new approaches and novel drug-like compounds are urgently needed to treat cardiovascular disease in California and elsewhere. The poor prognosis for heart disease for Californians underscores the critical need to develop alternative therapeutic strategies. The demonstrated ability of human embryonic stem cells (hESCs) to form cardiomyocytes has spawned widespread hope that these cells may be used as a source to replace damaged myocardium in humans. Despite their ability to form cardiomyocytes, efficient and controlled cardiomyogenesis in hESC culture has not been achieved due to the unavailability of differentiation agents and also because of an incomplete understanding of the pathways that regulate cardiac cell development. Using a high-throughput whole cell assay with image analysis, we have identified four small molecules that promote cardiomyogenesis in human ESCs. This proposal is directly responsive to the California Institute for Regenerative Medicine SEED Grant Program because it provides for developing and testing new agents of use in cardiomyogenesis of hESCs. It also brings new investigators and new collaborative approaches to the field. The promising agents discovered already constitute an excellent starting point and further refinement and development of these compounds may hold great promise as the groundwork for future medications development for a new class of damaged myocardium differentiation agents. The theoretical rationale for the work is the use of high-content screening coupled with drug-like new agent discovery approaches. The work will be of use in the elucidation of key biochemical targets and novel signaling pathways important in hESC cardiomyogenesis. The compounds discovered in our whole hESC-based assays thus far are not potent enough to be developed as drug candidates. But these compounds hold great promise as agents that could be refined further into drug leads. If the leads become drugs, promise of a new class of medication to treat cardiovascular disease may become a reality. Such drugs would decrease cardiovascular disease and decrease health care costs in California. This will likely have a significant economic impact to the State of California. The proposed work represents essential translational research required for new drug development.
Progress Report: 
  • The original goals of the proposal were to apply medicinal chemistry to generate more potent and drug-like analogs of small molecules that stimulate differentiation of cardiomyocytes from embryonic stem cell (ESC) and potentially other progenitor cell types found in adult human heart. During the grant period, we over-achieved each Aim and provided large numbers of drug-like small molecules for cardiomyocyte differentiation studies. In addition, other related information was gained that has considerably expanded our understanding related to developing regenerative medicines.
  • 1. Synthetic Chemistry: From an initial screen of thousands of compounds, six 'hits' were identified. Almost 1300 compounds were synthesized as analogs of these “hits” with the goal of generating more effective novel compounds as possible therapeutics for heart disease.
  • 2. Assay development and screening: Novel synthetic chemical analogs were studied in cell-based assays to evaluate potency of stimulating cardiac cell development relative to the starting 'hit' compounds. The biological data contributed to structure activity relationship (SAR) studies, and provided valuable information about parts of the molecules important for cardiomyocyte stem cell differentiation and for other important pharmaceutical properties. The iterative feedback from the biological testing helped to guide the next generation designs of new and ever more effective compounds.
  • 3. Chemical optimization. Focused structure activity relationship (SAR) studies for 4 chemical series from the ESC cardiogenesis differentiation screen were done. SAR for 2 additional chemical classes was done but those agents proved less potent. In addition to SAR, considerable information was obtained leading to improved solubility and membrane permeability of compounds in development, which became a focus of the chemical optimizations.
  • In summary, the work has already led to one or more promising drug-like compounds ready for efficacy testing in animal models and thus, efforts have greatly accelerated the timeline of getting compounds to human patients.
  • The original goals of the proposal were to apply medicinal chemistry to generate more potent and drug-like analogs of small molecules that stimulate differentiation of cardiomyocytes from embryonic stem cells (ESCs) and potentially other progenitor cell types found in adult human heart. During the grant period, we over-achieved each Aim and provided large numbers of drug-like small molecules for cardiomyocyte differentiation studies. In addition, other related information was gained that has considerably expanded our understanding related to developing regenerative medicines.
  • 1. Synthetic Chemistry: From an initial screen of thousands of compounds, six ‘hits’ were identified. Almost 1400 compounds were synthesized as analogs of these “hits” with the goal of generating more effective novel compounds as possible therapeutics for heart disease.
  • 2. Assay development and screening: Novel synthetic chemical analogs were studied in cell-based assays to evaluate potency of stimulating cardiac cell development relative to the starting ‘hit’ compounds. The biological data contributed to structure activity relationship (SAR) studies, and provided valuable information about parts of the molecules important for cardiomyocyte stem cell differentiation and for other important pharmaceutical properties. The iterative feedback from the biological testing helped to guide the next generation design of new and ever more effective compounds.
  • 3. Chemical optimization. Focused structure activity relationship (SAR) studies for 4 chemical series from the ESC cardiogenesis differentiation screen were done. SAR for 2 additional chemical classes was done but those agents proved less potent. In addition to SAR, considerable information was obtained leading to improved solubility and membrane permeability of compounds in development, which became a focus of the chemical optimizations. The most potent compounds increased stem cell differentiation to cardiomyocytes 5-10 fold. The compounds were non-toxic, reasonably tractable to make, stable and were water-soluble and hence relatively easy to handle.
  • 4. A number of biological signaling pathways were identified as affiliated with cardiomyocyte differentiation. One such pathway also is involved in anti-cancer activities. Thus, our efforts in identifying cardiomyocyte differentiation agents led us to study novel biology associated with cancer. One “hit” of this signaling pathway was chosen to do synthetic chemistry and “hit” to lead refinement. Approximately 100 compounds were synthesized and tested for inhibition of this signaling pathway.
  • In summary, the work has already led to a number of promising drug-like compounds ready for efficacy testing in animal models and thus, efforts have greatly accelerated the timeline of getting compounds to human patients. A total of 1500 compounds were synthesized to optimize the potency and properties of cardiomyocyte differentiation agents. The most potent stimulated production of human cardiomyocytes 5-10-fold compared to vehicle-stimulated cells.
Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01461
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$5 560 232
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Closed
Public Abstract: 
The adult human heart contains small numbers of cardiac stem cells that are able to partially repair the heart following a heart attack or throughout the course of progressive heart failure. We have developed a method to isolate these cells and grow them to large numbers in the lab. Isolation begins with a minimally-invasive biopsy taken from a patient’s heart. Our method can be used to then generate clusters of cells (termed “cardiospheres [CSps]”) or individual cells (termed “cardiosphere-derived cells [CDCs]”), each with their own advantages and disadvantages. When delivered to animals after a heart attack or in the midst of heart failure, these cells can better repair the heart, form new heart muscle and new blood vessels. CDCs are currently being given to patients after a recent heart attack, using a catheter to deliver the single cells into a blood vessel supplying the heart, as part of an ongoing clinical trial. The proposed research aims to test both CSps and CDCs in large animals in the midst of heart failure, using a catheter to deliver the cells directly into the heart muscle, in preparation for another clinical trial. Preliminary data shows that CSps may be a more potent cell therapeutic when compared to their single cell counterparts. Direct injection into the muscle not only allows for safe delivery of the cell clusters, but also increases the effective dose of the cells. Patients with heart failure also stand to benefit more from such a cell-based therapeutic when compared to those victims of a recent heart attack. As such, this research will involve not only animal studies, but also cell manufacturing studies, and the preparation and filing of an IND in order to begin a clinical trial. The first study will test both cell products along with the direct-injection catheter in a large scale animal model in order to determine the optimum cell dose. The second study will determine the optimum number of injections to perform during the procedure. These results will be available by the end of the first year, and will allow for a final pivotal study to be conducted during the course of the second year. This pivotal study will examine both the safety and efficacy of cell delivery in the large scale animal model, utilizing a group of control animals, and will serve as key preclinical data when filing an IND. During the course of the first two years, cell manufacturing studies will be conducted in parallel. These studies will enable us to develop procedures to reproducibly generate, store, ship, and deliver the cell therapeutic in the manner that will be adopted during the clinical trial. During the third year, the preclinical and manufacturing data will be combined with a clinical protocol formulated during the course of the pivotal animal study, to constitute the bulk of an IND. Following pre-IND discussions and IND review, we will begin conducting a clinical trial in patients with heart failure in the hope of halting disease progression for these individuals.
Statement of Benefit to California: 
Few families in California are not impacted by heart disease. Cardiovascular disease remains the leading cause of death and disability in Americans- on average, cardiovascular disease kills one American every 37 seconds. The death toll from cardiovascular disease is greater than that for cancer, chronic respiratory diseases, accidents, and diabetes combined. Death rates have improved, but new treatments are urgently needed. Aside from the human costs, cardiovascular disease exacts a tremendous fiscal toll: the American Heart Association estimates that the total costs of cardiovascular disease in the United States approached one-half trillion dollars in 2008. All taxpayers must bear the economic burden of resulting death and disability. Clearly, virtually all Californians stand to benefit, directly or indirectly, from the development of more effective treatments of cardiovascular disease. Heart disease is a particularly good target not just because of the magnitude of the public health problem, but also because heart muscle does not ordinarily regenerate once it has been destroyed by heart attacks and other types of damage. We seek to tap into the innate repair mechanisms of the heart by harvesting adult cardiac stem cells. The present work seeks to provide the scientific basis for regulatory filings that would allow us to reintroduce cardiac stem cells into patients with advanced heart failure. The treatment would be “autologous”, in that cells from any given patient would be used to treat that same patient. Thus, the cells are a perfect genetic match, obviating the risk of rejection. If our studies are successful, we may offer a cost-effective way to reduce the tremendous damage to Californians inflicted by major types of cardiovascular disease. This in turn may also reduce the economic burden presently borne by taxpayers who support the health care systems in California. In addition to the public health benefits, spinoff technology developed by this disease team will benefit existing California-based biotechnology companies, leading to fuller employment and an enhanced tax base.
Progress Report: 
  • Disease Team Award DR1-01461, Autologous cardiac-derived cells for advanced ischemic cardiomyopathy, is targeted at developing novel therapies for the treatment of heart failure, a condition which afflicts 7 million Americans. Heart failure, when symptomatic, has a mortality exceeding that of many malignant tumors; new therapies are desperately needed. In the first year of CIRM support, we have developed and validated a development candidate, cardiospheres, which are three-dimensional (3D) functional microtissues engineered in culture and suitable for implantation in the hearts of patients via minimally-invasive catheter-based methods. Cardiospheres, derived from heart biopsies using methods developed by the Principal Investigator, have now been successfuly delivered via magnetically-navigated injection catheters into healthy heart tissue surrounding zones of myocardial damage in preclinical models. The 3D microtissues engraft efficiently in preclinical models of heart failure, as expected from prior work indicating their complex multi-layer nature combining cardiac progenitors, supporting cells and derivatives into the cardiomyocyte and endothelial lineages. We have also developed standard operating procedures for cardiosphere manufacturing, and are in the process of developing release criteria for the 3D microtissue development candidate. Next steps include efficacy studies, with a view to an approved IND by mid-2012.
  • Disease Team Award DR1-01461, autologous cardiac-derived cells for advanced ischemic cardiomyopathy, is targeted at developing novel therapies for the treatment of heart failure, a condition which afflicts 7 million Americans. Heart failure, when symptomatic, has a mortality exceeding that of many malignant tumors; new therapies are desperately needed. In the second year of CIRM support, pivotal pre-clinical studies have been completed. We have found that dose-optimized injection of CSps preserves systolic function, attenuates remodeling, decreases scar size and increases viable myocardium in a porcine model of ischemic cardiomyopathy. The 3D microtissues engraft efficiently in preclinical models of heart failure, as expected from prior work indicating their complex multi-layer nature combining cardiac progenitors, supporting cells and derivatives into the cardiomyocyte and endothelial lineages. Analysis of the MRI data continues. We have developed standard operating procedures for cardiosphere manufacturing and release criteria, product and freezing/thawing stability testing have been completed for the 3D microtissue development candidate. We have identified two candidate potency assays for future development. The disease team will evaluate the results of the safety study (immunology, histology, and markers of ischemic injury) and complete the pivotal pig study in Q1 2012. With data in hand, full efforts will be placed on preparation of the IND for Q2 2012 submission.
Funding Type: 
Basic Biology I
Grant Number: 
RB1-01354
Investigator: 
ICOC Funds Committed: 
$1 378 076
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Closed
Public Abstract: 
For the millions of Americans who are born with or develop heart disease, stem cell research offers the first hope of reversing or repairing heart muscle damage. Thus, early reports suggesting heart regeneration after transplantation of adult bone marrow-derived stem cells were met with great excitement in both the scientific and lay community. However, although adult stem cell transplantation was shown to be safe, results from over a dozen clinical trials concluded that the benefits were modest at best and whether any true regeneration is occurring was questionable. The basis for these disappointing results may be related to poorly characterized cell types used that have little capacity for true regeneration and an inadequate understanding the factors necessary for survival and differentiation of transplanted stem cells. In this application, we are proposing to study the growth and differentiation properties of an authentic endogenous human cardiac progenitor cell that can differentiate into cardiac muscle cells, smooth muscle cells and endothelial cells. We will also determine the factors that support its growth and renewal during normal development. This knowledge will be applied to future clinical trials of cardiovascular cell therapy that allow truly regenerative therapy.
Statement of Benefit to California: 
Heart disease, stroke and other cardiovascular diseases are the #1 killer in California. Despite medical advances, heart disease remains a leading cause of disability and death. Recent estimates of its cost to the U.S. healthcare system amounts to almost $300 billion dollars. Although current therapies slow the progression of heart disease, there are few, if any options, to reverse or repair damage. Thus, regenerative therapies that restore normal heart function would have an enormous societal and financial impact not only on Californians, but the U.S. more generally. The research that is proposed in this application could lead to new therapies that would restore heart function after and heart attack and prevent the development of heart failure and death.
Progress Report: 
  • In this application, we propose to study the growth and differentiation properties of an authentic endogenous human cardiac progenitor cells (CPCs) that can differentiate into cardiac muscle cells, smooth muscle cells and endothelial cells. We have isolated these multipotent CPCs from human ventricles and human induced pluripotent cells and compared therie differentiation potential. Additionally, we have characterized a cardiac niche in the developing heart, demonstrated that both the extracellulat matrix molecules and the three dimensional environment is important for CPC renewal. We believe these experiments will significantly advance out understanding of the biology of CPCs and facilitate their application as a regenerative therapy.
  • In this application, we propose to study the growth and differentiation properties of an authentic endogenous human cardiac progenitor cells (CPCs) that can differentiate into cardiac muscle cells, smooth muscle cells and endothelial cells. We have isolated these multipotent CPCs from human ventricles and human induced pluripotent cells and compared therie differentiation potential. Additionally, we have characterized a cardiac niche in the developing heart, demonstrated that both the extracellulat matrix molecules and the three dimensional environment is important for CPC
  • renewal. We believe these experiments will significantly advance out understanding of the biology of CPCs and facilitate their application as a regenerative therapy.

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