Heart Disease

Coding Dimension ID: 
295
Coding Dimension path name: 
Heart Disease

Generation and characterization of high-quality, footprint-free human induced pluripotent stem cell lines from 3,000 donors to investigate multigenic diseases

Funding Type: 
hiPSC Derivation
Grant Number: 
ID1-06557
ICOC Funds Committed: 
$16 000 000
Disease Focus: 
Developmental Disorders
Genetic Disorder
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Induced pluripotent stem cells (iPSCs) have the potential to differentiate to nearly any cells of the body, thereby providing a new paradigm for studying normal and aberrant biological networks in nearly all stages of development. Donor-specific iPSCs and differentiated cells made from them can be used for basic and applied research, for developing better disease models, and for regenerative medicine involving novel cell therapies and tissue engineering platforms. When iPSCs are derived from a disease-carrying donor; the iPSC-derived differentiated cells may show the same disease phenotype as the donor, producing a very valuable cell type as a disease model. To facilitate wider access to large numbers of iPSCs in order to develop cures for polygenic diseases, we will use a an episomal reprogramming system to produce 3 well-characterized iPSC lines from each of 3,000 selected donors. These donors may express traits related to Alzheimer’s disease, autism spectrum disorders, autoimmune diseases, cardiovascular diseases, cerebral palsy, diabetes, or respiratory diseases. The footprint-free iPSCs will be derived from donor peripheral blood or skin biopsies. iPSCs made by this method have been thoroughly tested, routinely grown at large scale, and differentiated to produce cardiomyocytes, neurons, hepatocytes, and endothelial cells. The 9,000 iPSC lines developed in this proposal will be made widely available to stem cell researchers studying these often intractable diseases.
Statement of Benefit to California: 
Induced pluripotent stem cells (iPSCs) offer great promise to the large number of Californians suffering from often intractable polygenic diseases such as Alzheimer’s disease, autism spectrum disorders, autoimmune and cardiovascular diseases, diabetes, and respiratory disease. iPSCs can be generated from numerous adult tissues, including blood or skin, in 4–5 weeks and then differentiated to almost any desired terminal cell type. When iPSCs are derived from a disease-carrying donor, the iPSC-derived differentiated cells may show the same disease phenotype as the donor. In these cases, the cells will be useful for understanding disease biology and for screening drug candidates, and California researchers will benefit from access to a large, genetically diverse iPSC bank. The goal of this project is to reprogram 3,000 tissue samples from patients who have been diagnosed with various complex diseases and from healthy controls. These tissue samples will be used to generate fully characterized, high-quality iPSC lines that will be banked and made readily available to researchers for basic and clinical research. These efforts will ultimately lead to better medicines and/or cellular therapies to treat afflicted Californians. As iPSC research progresses to commercial development and clinical applications, more and more California patients will benefit and a substantial number of new jobs will be created in the state.

Tissue Collection for Accelerating iPSC Research in Cardiovascular Diseases

Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06596
Investigator: 
ICOC Funds Committed: 
$1 435 371
Disease Focus: 
Heart Disease
oldStatus: 
Active
Public Abstract: 
Heart failure is a very common and chronic condition defined by an inability of the heart to pump blood effectively. Over half of cases of heart failure are caused by a condition called dilated cardiomyopathy, which involves dilation of the heart cavity and weakening of the muscle. Importantly, many cases of this disease do not have a known cause and are called “idiopathic” (i.e., physicians do not know why). Over the past 2 decades, doctors and scientists started realizing the disease can cluster in families, leading them to think there is a genetic cause to the disease. This resulted in discovering multiple genes that cause this disease. Nonetheless, the majority of cases of dilated hearts that cluster in families do not have a known genetic cause. Now scientists can turn blood and skin cells into heart cells by genetically manipulating them and creating engineered stem cells called “induced pluripotent stem cells” or iPSCs. This approach enables the scientists to study what chemical or genetic changes are happening to cause the problem. Also because these cells behave similar to the cells in the heart, scientists can now test new medicines on these cells first before trying them in patients. Here we aim to collect tissue from 800 patients without a known cause for their dilated hearts (and 200 control individuals) to help accelerate our understanding of this debilitating disease and hopefully offer new and better treatments.
Statement of Benefit to California: 
Heart failure is a significant health burden in California with rising hospitalization and death rates in the state. We have a very limited understanding of the disease and so far the existing treatments only slow down the disease and the changes that happen rather than target the root cause. By studying a subgroup of the dilated cardiomyopathy patients who have no identified cause, we can work on identifying genetic causes of the disease, some of the biology happening inside the heart cell, and provide new treatments that can prevent the disease from happening or progressing. Improving the outcome of this debilitating disease and providing new treatments will go a long way to helping a large group of Californians lead healthier and longer lives. There are estimates that the US economy loses $10 billion (not counting medical costs), because heart failure patients are unable to work. Hence new knowledge and developments gained from this research can go a long way to ameliorating that cost. Finally, heart failure is the most common chronic disease patients in California are hospitalized for. This research targets over half of those admissions. If this research is able to cut the hospitalization rate even by 1%, this would translate to millions of dollars in savings to the state. Continuing to invest in innovation will make our state a hotbed for the biotechnology industry, which in turn advances the state’s economic and educational status.
Progress Report: 
  • Heart failure is a leading cause of morbidity and mortality in California and the Western world with a significant economic burden due to the disease. Over half of heart failure cases are due to dilated cardiomyopathy, a disorder of progressive ventricular dilation and decreased contractility. However, after ischemic cardiomyopathy, the majority of familial cases of dilated cardiomyopathy are unknown or "idiopathic", suggesting a polygenic etiology with a complex genetic-environmental interaction. Traditionally, studying this disorder has been impaired by inability to access cardiac tissue and the limitation of mouse models in recapitulating the disorder. Thus, we propose using human induced pluripotent stem cells (iPSCs) to study idiopathic familial dilated cardiomyopathy (IFDC). We propose collecting tissue from individuals identified with the disorder In summary, this proposal represents a unique
  • opportunity to improve our understanding of idiopathic familial dilated cardiomyopathy (which remains largely a mystery), identifying novel genetic causes (rendering many of these patients no longer “idiopathic), and proposing new therapeutic targets.

Mechanism of heart regeneration by cardiosphere-derived cells

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06215
ICOC Funds Committed: 
$1 367 604
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
In the process of a heart attack, clots form suddenly on top of cholesterol-laden plaques, blocking blood flow to heart muscle. As a result, living heart tissue dies and is replaced by scar. The larger the scar, the higher the chance of premature death and disability following the heart attack. While conventional treatments aim to limit the initial injury (by promptly opening the clogged artery) and to prevent further damage (using various drugs), regenerative therapy for heart attacks seeks to regrow healthy heart muscle and to dissolve scar. To date, cell therapy with CDCs is the only intervention which has been shown to be clinically effective in regenerating the injured human heart. However, the cellular origin of the newly-formed heart muscle and the mechanisms underlying its generation remain unknown. The present grant seeks to understand those basic mechanisms in detail, relying upon state-of-the-art scientific methods and preclinical disease models. Our work to date suggests that much of the benefit is due to an indirect effect of transplanted CDCs to stimulate the proliferation of surrounding host heart cells. This represents a major, previously-unrecognized mechanism of cardiac regeneration in response to cell therapy. The proposed project will open up novel mechanistic insights which will hopefully enable us to boost the efficacy of stem cell-based treatments by bolstering the regeneration of injured heart muscle.
Statement of Benefit to California: 
Coronary artery disease is the predominant cause of premature death and disability in California. Clots form suddenly on top of cholesterol-laden plaques in the wall of a coronary artery, blocking blood flow to the heart muscle. This leads to a “heart attack”, in which living heart muscle dies and is replaced by scar. The larger the scar, the greater the chance of death and disability following the heart attack. While conventional treatments aim to limit the initial injury (by promptly opening the clogged artery) and to prevent further injury (using various drugs), regenerative therapy for heart attacks seeks to regrow healthy heart muscle and to dissolve scar. To date, cell therapy with CDCs is the only intervention that has been shown to be clinically effective in regenerating the injured human heart. However, the cellular origin of the newly-formed heart muscle and the mechanisms underlying its generation remain unknown. The present grant seeks to understand those basic mechanisms in detail, relying upon state-of-the-art scientific methods and preclinical disease models. The resulting insights will enable more rational development of novel therapeutic approaches, to the benefit of the public health of the citizens of California. Economic benefits may also accrue from licensing of new technology.
Progress Report: 
  • Key abbreviations:
  • CDCs: cardiosphere-derived cells
  • MI: myocardial infarction
  • The present award tests the hypothesis that CDCs promote regrowth of normal mammalian heart tissue through induction of adult cardiomyocyte cell cycle re-entry and proliferation (as occurs naturally in zebrafish and neonatal mice). Such a mechanism, if established, would challenge the dogma that terminally-differentiated adult cardiomyocytes cannot re-enter the cell cycle. We have employed an inducible cardiomyocyte-specific fate-mapping approach (to specifically mark resident myocytes and their progeny), coupled with novel methods of myocyte purification and rigorous quantification. We have also developed assays that enable us to exclude potential technical confounding factors. The use of bitransgenic mice is essential for our experimental design (as it enables fate mapping of resident myocytes in a mammalian model), while the use of mouse CDCs in our in vivo experiments (as opposed to human CDCs) enables us to avoid immunosuppression and its complications. To date, mouse, rat and pig models have proven to be reliable in predicting clinical effects of CDC therapy in humans, and results with human and mouse CDCs in comparable models (e.g., SCID mice for human CDCs versus wild-type mice for mouse CDCs) have not revealed any major mechanistic divergence. Our results demonstrate that induction of cardiomyocyte proliferation represents a major, previously-unrecognized mechanism of cardiac regeneration in response to cell therapy. One full-length publication describing these findings has appeared (K. Malliaras et al., EMBO Mol Med, 2013, 5:191-209), and another paper has been submitted. The work has already begun to open up novel mechanistic insights which will enable us to improve the efficacy of stem cell-based treatments and bolster cardiomyocyte repopulation of infarcted myocardium.

Human ES cell based therapy of heart failure without allogenic immune rejection

Funding Type: 
Early Translational III
Grant Number: 
TR3-05559
ICOC Funds Committed: 
$1 857 600
Disease Focus: 
Heart Disease
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Heart failure is a major and ever-growing health problem affecting an estimated 5.8 million Americans with about half a million new cases every year. There are limited therapeutic options for heart failure. Heart transplantation is effective but has limited impact due to scarcity of donor organs and eventual immune rejection even under chronic immune suppression. Therefore, there is a clear unmet medical need to develop new effective therapies to treat heart failure. Human ES cell based cell therapy could provide a cure for heart diseases by providing renewable source of human cardiomyocytes (CMs) to restore lost cardiomyocytes and cardiac functions. In support of this notion, hESC-derived cardiomyocytes (hESC-CMs) can repopulate lost cardiac muscle and improve heart function in preclinical animal models of advanced heart failure. However, one key bottleneck hindering such clinic development is that hESC-CMs will be rejected by allogenic immune system of the recipients, and the typical immunosuppressant regimen is especially toxic for patients with heart diseases and leads to increased risk of cancer and infection. To resolve this bottleneck, I propose to develop a novel approach to protect the hESC-CMs from allogenic immune system. If successful, our approach will not only greatly improve the feasibility of developing hESC-CMs to treat heart failure but also has broad application in other hESC-based cell therapies for which allogenic immune rejection remains a major hurdle.
Statement of Benefit to California: 
Heart disease is a leading cause of death and disability among Californians with an above average rate of mortality. It costs the State tremendous expenditure for the treatment and loss of productivity. There are limited therapeutic options for advanced heart diseases. In this context, heart transplantation is effective but limited by the shortage of donors. Therefore, there is clearly an urgent unmet medical need for new and effective therapies to treat heart failure. Human ES cell based cell therapy approach offers the unique potential to provide renewable source of cardiomyocytes to treat heart failure by restoring lost cardiomyocytes and cardiac function. However, one key bottleneck is that the allogenic hESC-derived cardiomyocytes will be immune rejected by recipients, and the typical immunosuppression regimen is especially toxic for fragile patients with heart diseases. In addition, chronic immune suppression greatly increases the risk of cancer and infection. Our proposed research is aimed to develop novel strategies to prevent allogenic immune rejection of hESC-derived cardiomyocytes without inducing systemic immune suppression. If successful, our approach will greatly facilitate the development of hESC-derived cardiomyocytes for treating heart disease and also has broad application in other hESC-based therapy for which allogenic immune rejection remains a bottleneck.
Progress Report: 
  • Heart failure affects an estimated 5.8 million Americans with about half a million new cases every year. It is also one of the leading causes of death and loss of productivity in California. There is a clear unmet medical need to develop new therapies to treat patients with heart failure. Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and retain the pluripotency to differentiate into all cell types in the body. Therefore, as a renewable source of various cell types in the body, hESCs hold great promise for the cell replacement therapy of many human diseases. In this context, significant progress has been made in the differentiation of hESCs into functional cardiomyocytes (CMs), providing the potential of cell replacement therapy to cure heart diseases through the restoration of lost cardiac function. However, one key bottleneck hindering the clinic development of hESC-derived CMs is that hESC-derived CMs will be rejected by allogenic immune system of the recipients, and the typical immunosuppressant regimen can be highly toxic for patients with heart diseases. To resolve this bottleneck and improve the feasibility of the hESC-based therapy of heart failure, we developed and validated a novel approach to protect the hESC-derived CMs from the allogenic human immune system in vivo.
  • Heart failure is a major disease in California with limited therapeutic options. It costs the State tremendous expenditure in treatment and loss in productivity. While heart transplant is effective in treating the disease, this option is limited by the scarcity of heart donors and the modest graft survival rate (50%) ten years after transplantation. With their unlimited self-renewal capability and pluripotency to differentiate into all cell types in the body, human ES cells (hESCs) hold great promise for human cell therapy. Therefore, cell therapy approaches with hESC-derived CMs have the unique potential for a cure by restoring lost CMs and cardiac function. Despite significant progress in differentiating hESCs into CMs that are capable of partially restoring heart functions in myocardia infarction (MI) animal models, one key bottleneck remaining is that the allogenic hESC-derived CMs will be immune rejected by the recipients, and the typical immunosuppression regimen is especially toxic for patients with advanced heart diseases. By developing a novel approach to prevent allogenic immune rejection of hESC-derived CMs without the typical immunosuppression, we showed that genetically modified hESCs can be efficiently differentiated into cardiomyocytes, which exhibit characteristic electric physiological properties and are protected from allogenic immune rejection.

Extracellular Matrix Bioscaffold Augmented with Human Stem Cells for Cardiovascular Repair

Funding Type: 
Early Translational III
Grant Number: 
TR3-05626
ICOC Funds Committed: 
$4 939 140
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
An estimated 16.3 million Americans suffer from coronary heart disease. Every 25 seconds, someone has a coronary event and every minute, someone dies from one. Treatment for coronary heart disease has improved greatly in recent years, yet 1 in 6 deaths in the US in 2007 was still caused by this terrible disease. Stem cells have been used as an supplemental form of treatment but they have been most effective for patients treated immediately after their first heart attack. Unfortunately, stem cell therapy for chronic heart disease and heart failure has been less successful. With current delivery methods for stem cells into the heart, most are washed away quickly, whereas our device will hold them in the area that needs repair. With this project we are testing a novel approach to improve the benefits of stem cell therapy for patients suffering from chronic heart disease. By applying a type of bone marrow stem cells known to enhance tissue repair (mesenchymal stem cells) to a biological scaffold, we hope to greatly amplify the beneficial properties of both the stem cells and the biological scaffold. This device will be implanted onto an appropriate preclinical model that have been treated so as to mirror the chronic heart disease seen in humans. We predict that this novel device will heal the damaged heart and improve its function to pave the way for a superior treatment option for the thousands of Americans for whom the unlikely prospect of a heart transplant is currently the only hope.
Statement of Benefit to California: 
Heart disease is the number one cause of death and disability in California and in the US as a whole. An estimated 16.3 million Americans over the age of 20 suffer from coronary heart disease (CHD) with an estimated associated cost of $177.5 billion and CHD accounted for 1 in 6 deaths in the US in 2007. Advances in treatment have decreased early mortality but consequently lead to an increase in the incidences of heart failure (HF). Patients with HF have a 50 percent readmission rate within six months, which is a heavy cost both in terms of quality of life and finances. The high cost of caring for patients with HF results primarily from frequent hospital readmissions for exacerbations. The need for efficient treatment strategies that address the underlying cause, massive loss of functional myocardium, is yet to be met. We believe that present project proposal, development of a combined mesenchymal stem cell and extra cellular matrix scaffold device, will lead to improved standards of care for patients suffering from chronic myocardial infarction who are thus at risk of developing HF. By not only retarding disease progression but by actually restoring cardiac function, we believe that the proposed project will have a tremendous impact on both the cost of care as well as the quality of life for large groups of Californians and patients worldwide for whom the improbable prospect of heart transplantation is the only curative treatment option available.
Progress Report: 
  • Heart disease is a major cause of death and disability in the US, accounting for 1 in every 4 deaths and costing more than 100 billion annually. While significant improvements have been made towards treating and managing heart disease, we are still not able to effectively return the heart to a healthy state and cure the patients. With our project we have set out to develop a novel strategy for not only halting the disease progression but to reverse the devastating effect on the function of the heart. By combining bone marrow mesenchymal stromal cells with a biological scaffold material, we hope to create a patch for the heart that will support and regenerate the diseased tissue to the point where the patient will be relieved of the burden of their disease and have a markedly improve quality of life. We have in the past year made significant advances toward establishing an animal disease model in which we can study novel ways of treating heart disease. We have in the same time isolated and characterized cells that reside in the bone marrow and that have the potential to heal the diseased tissue by improving blood flow, minimize scarring and generally promoting recovery of the heart function. We have studies these cells under when grown under different conditions and found their ability to mediate tissue regeneration to be highly dependent on their local environments. We are currently trying to identify the optimal combination of cells and microenvironment that may achieve maximal regenerative effect in our disease model and ultimately help our patient combat their heart disease.

Direct Cardiac Reprogramming for Heart Regeneration

Funding Type: 
Early Translational III
Grant Number: 
TR3-05593
ICOC Funds Committed: 
$6 319 110
Disease Focus: 
Heart Disease
Stem Cell Use: 
Directly Reprogrammed Cell
oldStatus: 
Active
Public Abstract: 
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 preclinical model of cardiac injury, and to establish the safety profile of in vivo cardiac reprogramming in a preclinical model.
Statement of Benefit to California: 
This research will benefit the state of California and its citizens by helping develop a new therapeutic approach to cardiac regeneration. Heart disease is a leading cause of death in adults and children in California, but there is no current treatment that can promote cardiac regeneration. This proposal will lay the groundwork for a clinical trial that could result in generation of new heart muscle cells from within the heart. If successful, there is potential economic benefit in terms of productive lives saved and in the commercialization of this technology.
Progress Report: 
  • 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.

Preclinical Development and First-In-Human Testing of [REDACTED] in Advanced Heart Failure

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05434
ICOC Funds Committed: 
$106 239
Disease Focus: 
Heart Disease
oldStatus: 
Closed
Public Abstract: 
This application seeks to bring to the clinic a new treatment for myocardial disease based on human embryonic stem cell (hESC) derived cardiomyocytes. hESC-cardiomyocytes have the unique potential to address the underlying cause of heart disease by repopulating areas of damaged myocardium (heart tissue) with viable cardiac cells. This therapeutic approach represents a potential breakthrough in heart disease treatment, serving one of the most intractable, largest, and most costly unmet clinical needs in the U.S. Currently available heart disease treatments have demonstrated ability to slow progression of the disease, but to date none can restore the key underlying defect in heart failure, a loss of contractile function. Cell therapy approaches have generated excitement for their unique potential to play a curative role in myocardial disease through the restoration of lost contractile and/or circulatory function. hESC-cardiomyocytes are unique amongst the cell therapy approaches in that they are a human cardiomyocyte (heart muscle cell) product; replacing damaged myocardium with viable heart cells which can integrate and form fully functional cardiac tissue. This approach has the potential to significantly halt or reverse cardiac functional decline. These benefits can significantly impact patient medication requirements and hospitalizations associated with ongoing cardiac decline, key drivers of the enormous health care costs associated with heart failure. The proposed scope of this project includes activities leading up to and including a regulatory filing with the FDA to initiate clinical testing of hESC-cardiomyocytes for the treatment of heart failure, as well as the enrollment and initial follow-up of a small cohort of patients in a first-in-human trial. The proposed product has completed extensive process development, product characterization, and preclinical (animal model studies) proof-of-concept studies to date. The scope of the proposed research includes: (i) performance of key preclinical safety and efficacy studies to enable entry to clinical testing (ii) manufacture of material for use in preclinical studies, development work, and clinical testing (iii) development and qualification of assays for product characterization, and (iv) preparation for and execution of initial clinical studies.
Statement of Benefit to California: 
The proposed project has the potential to benefit the state of California through 1) providing improved medical outcomes for patients with heart disease, 2) increasing California’s leadership in the emerging field of stem cell research, and 3) preserving and creating high quality, high paying jobs for Californians. Heart disease is one of the most intractable, wide-spread, and fatal diseases in the U.S. More than 5.8 million Americans currently suffer from heart failure; close to 60% of heart failure patients die within 5 years of diagnosis. Although specific statistics are not available for California, they are likely similar to those nationwide, with incidence of more than 10 in 1000 individuals >65 years of age (AHA, 2010). Currently available heart disease therapies have demonstrated the ability to slow disease progression, but to date none can restore the key underlying defect leading to heart failure, a loss of cardiac contractile function. Cell therapy, an approach to regenerate or repair the damaged heart with new cells, addresses this fundamental need, and is considered one of the most important and promising frontiers for the treatment of heart disease. Although multiple other cell therapy products are currently being evaluated for the treatment of heart disease, human embryonic stem cell derived cardiomyocytes have unique potential to address the underlying defect of loss of contractile activity in heart failure, by replacing scarred or damaged heart tissue with new, functional human heart cells to restore cardiac function. California has a history of leadership in biotechnology, and is emerging as a leader in the development of stem cell therapeutics. Cutting edge stem cell research, in many cases funded by CIRM, is already underway in academic research laboratories and biotechnology companies throughout the state. The proposed project has the potential to further increase California’s leadership in the field of stem cell therapeutics through the performance of the first clinical testing of an hESC-derived cardiac cell therapy. The applicant has been located in California since its inception, and currently employs nearly 200 full-time employees at its California headquarters with more than 50% of employees holding an advanced degree. These positions are highly skilled positions, offering competitive salaries and comprehensive benefits. The successful performance of the proposed project would enable significant additional jobs creation as the program progresses through more advanced clinical testing.

Molecular Mechanisms Underlying Human Cardiac Cell Junction Maturation and Disease Using Human iPSC

Funding Type: 
Basic Biology III
Grant Number: 
RB3-05103
ICOC Funds Committed: 
$1 341 955
Disease Focus: 
Heart Disease
Pediatrics
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Heart disease is the number one cause of death and disability in California and in the United States. Especially devastating is Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), an inherited form of heart disease associated with a high frequency of arrhythmias and sudden cardiac death in young people, including young athletes, who despite their appearance of health are struck down by this type of heart disease. Even though it is inherited, early detection is hindered because people carrying the genetic code have highly variable clinical symptoms, making ARVC and catastrophic cardiac events very hard to predict and avoid. Evidence suggests that this heart disease is caused by mistakes in the genetic code essential for holding the mechanical integrity of heart muscle cells together or cell junctions. What is missing is an understanding of the basic biology of these heart muscle cell junctions in humans and appropriate human model systems to study their dynamics in heart disease, which is important since other heart diseases also share some of these same heart cell defects. Our goal is to understand the basic biology of how human heart muscle cell junctions mature and what happens in disease, by studying ARVC. Human iPS cells are a unique population of stem cells from our own tissues, such as skin, that have the same genetic information as the rest of our bodies. Thus, hiPS from people who carry the ARVC heart disease mistakes can be used in our laboratory to provide a true human model of that disease. We will generate heart muscle cells from hiPS from normal and ARVC donors that carry mistakes in the genetic code for cell junction components. We have identified new pathways that may be important causes of ARVC, thus we will also use our hiPS lines, to confirm whether these new pathways are truly important in human ARVC disease progression and if our approaches reverse disease progression. Characterization of our hiPS derived heart cells can also be exploited for translational medicine to predict an individual's heart cell response to drug treatment and provides a promising platform to identify new drugs for heart diseases, such as ARVC, which are currently lacking in the field. Recent advances in stem cell biology have highlighted the unique potential of hiPS to be used in the future as a source of cells for cell-based therapies for heart disease. However, prior to clinical application, a detailed understanding of the basic biology and maturation of these hiPS into heart muscle cells is required. Our studies seek to advance our understanding of how cell-cell junctions mature in hiPS and highlight tools that influence the microenvironment of the hiPS in a dish, to accelerate this process. This knowledge can also be exploited in regenerative medicine to achieve proper electromechanical integration of cardiac stem cells when using stem cells for heart repair, to improve longterm successful clinical outcomes of cardiac stem cell therapies.
Statement of Benefit to California: 
Heart disease is the number one cause of death and disability within the United States and the rates are calculated to be even higher for citizens of the State of California when compared to the rest of the nation. These diseases place tremendous financial burdens on the people and communities of California, which highlights an urgency to understand the underlying molecular basis of heart diseases as well as find more effective therapies to alleviate these growing burdens. Our goal is to improve heart health and quality of life of Californians by generating human stem cell models from people with an especially devastating form of genetic heart disease that affects young people and results in sudden cardiac death, to improve our molecular and medical understanding of how cardiac cells go wrong in the early stages of heart disease in humans. We will also test current drugs used to treat heart disease and new candidate pathways, that we have uncovered, to determine if and how they reverse and intervene with these defects. We believe that our model systems have tremendous potential in being used to diagnose, test an individual's heart cell's response to drug treatment, as well as predict severity of symptoms in heart diseases at an early stage, to monitor drug treatment strategies for the heart. We believe our studies also have a direct impact on regenerative medicine as a therapy for Californians suffering from heart disease, since data from our studies can identify ways to improve cardiac stem cell integration into the diseased heart when used for repair, as a way to improve long-term successful clinical outcomes of cardiac stem cell therapies. We also believe that our development of multiple human heart disease stem cells lines with unique genetic characteristics could be of tremendous value to biotechnology companies and academic researchers interested in large scale drug screening strategies to identify more effective compounds to rescue defects and treat Californians with heart disease, as well as provide important economic revenue and resources to California, which is stimulated by the development of businesses interested in developing these therapies further.
Progress Report: 
  • Heart disease is the number one cause of death and disability in California and in the United States. Especially devastating is Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), an inherited form of heart disease associated with a high frequency of arrhythmias and sudden cardiac death in young people, including young athletes, who despite their appearance of health are struck down by this type of heart disease. Even though it is inherited, early detection is hindered because people carrying the genetic code have highly variable clinical symptoms, making ARVC and catastrophic cardiac events very hard to predict and avoid. Evidence suggests that this heart disease is caused by mistakes in the genetic code essential for holding the mechanical integrity of heart muscle cells together or cell junctions. What is missing is an understanding of the basic biology of these heart muscle cell junctions in humans and appropriate human model systems to study their dynamics in heart disease, which is important since other heart diseases also share some of these same heart cell defects. Our goal is to understand the basic biology of how human heart muscle cell junctions mature and what happens in disease, by studying ARVC. Human iPS cells are a unique population of stem cells from our own tissues, such as skin, that have the same genetic information as the rest of our bodies. Thus, hiPS from people who carry the ARVC heart disease mistakes can be used in our laboratory to provide a true human model of that disease. During the first year of our grant, we have enrolled sufficient numbers of normal and ARVC donors into our study. We have collected skin biopsy tissues from donors as means to generate hiPS cells. Our results show that hiPS cell lines can be efficiently generated from both normal and ARVC donors and we have extensively characterized their profiles, such that we know they are bona fide stem cell lines and can be used as a model system to dissect defects in cardiac cell junction biology between these various different hiPS lines. We have also developed efficient and robust methodologies to generate heart muscle cells from hiPS from normal and ARVC donors that carry mistakes in the genetic code for cell junction components and are now in the midst of characterizing their molecular, genetic, biochemical and functional profiles to identify features in these cells that are unique for ARVC. Through our previous studies, we identified new pathways that may be important causes of ARVC, thus we will also use our hiPS lines, to confirm whether these new pathways are truly important in human ARVC disease progression and if our approaches reverse disease progression. Towards this goal, we have generated novel tools to increase and decrease a component of this pathway in order to test these approaches and have preliminary data to show that these tools are efficient in altering levels of this component in heart muscle cells, which we are now applying towards understanding these pathways in hiPS derived heart muscle cells and reversing defects in heart muscle cells from ARVC hiPS derived lines. Based on our progress, we have met all of the milestones stated in our grant proposal and in some cases, surpassed some milestones. We believe progress over the next year, will allow us to define some of the key cellular defects in ARVC and advance our understanding of how cell-cell junctions mature in hiPS and highlight tools that influence the microenvironment of the hiPS in a dish, to accelerate this process.
  • Overall, we have been able to achieve the milestones proposed for Year 2 of the grant. We have generated a panel of control and ARVC hiPSC lines using integration-free based methods. We provide evidence of our method to generate robust numbers of hiPSC-derived cardiac cells that express desmosomal cell-cell junction proteins. We show ARVC lines that display disease symptom-specific features (adipogenic or arrhythmic), which phenocopy the striking and differential symptoms found in respective individual ARVC-patients as tools to study human ARVC. We also uncover desmosomal defects in hiPSC-derived cardiac muscle cells that underlie the disease features found in ARVC cells. We have also published two reviews in the field of cell-cell junctional remodeling and stem cell approaches that helps to further our understanding of this field in cardiomyocytes, that is relevant to human disease and our research using hiPS.
  • Overall, we have been able to complete the milestones proposed for our grant. We have generated a unique panel of control and ARVC hiPSC lines using integration-free methods. We provide evidence of our method to generate robust numbers of hiPSC derived cardiac cells that express key components of the cardiac muscle cell-cell junction include mechanical junctions and electrical junctions. We show that our ARVC hiPSC lines display disease symptom-specific features (adipogenic and arrhythmic), which phenocopy the striking and differential diagnosis observed in our ARVC donor hearts and provide a platform to study the varying disease features underlying ARVC. We uncover novel and classic molecular and ultrastructural defects underlying the arrhythmogenic defects in our ARVC hiPSC lines that mimic the gradation in disease severity observed in ARVC donor hearts. We exploit conventional ARVC drugs to determine their impact on arrhythmogenic behavior and reversibility of phenotypes in our cells. We have published 4 articles in the field of cell-cell junction remodeling, protein turnover and stem cell approaches that further our understanding of this field in cardiac muscle cells as well as filed a provisional patent application on the use of a novel drug discovery system for fat arrhythmogenic disorders that exploit the genetic diversity and clinical features observed in our ARVC lines.

A Novel Engineered Niche to Explore the Vasculogenic Potential of Embryonic Stem Cells

Funding Type: 
New Faculty I
Grant Number: 
RN1-00566
ICOC Funds Committed: 
$2 108 683
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Cardiovascular diseases account for an estimated $330 billion in health care costs each year, afflict 61.8 million Americans, and will account for more than 1.5 million deaths in the U.S. this year alone. A number of these diseases are characterized by either insufficient blood vessel growth or damage to the existing vessels, resulting in inadequate nutrient and oxygen delivery to the tissues. The most common clinical example of this is a heart attack, or myocardial infarction, typically caused by blockage of a coronary artery. The resulting ischemia (reduced blood flow) induces irreversible damage to the heart, leaving behind a non-functional scar tissue. Efforts to restore blood flow to ischemic tissues have largely focused on the delivery of protein growth factors (called pro-angiogenic molecules) that stimulate new capillary growth. An alternative approach is to deliver an appropriate cell type that can either accelerate the recruitment of host vessels or can differentiate into a functional vasculature directly. While adult stem cells have shown promising potential with respect to the former, the potential of embryonic stem cells (ESCs) with respect to either of these two possibilities remains unclear. Therefore, this proposal seeks to: 1.) Utilize a novel, highly tunable, 3D engineered niche to investigate how changes in multiple instructive signals coordinately govern the differentiation of ESCs into capillary vessels; 2.) Exploit knowledge gained from basic studies using this model system to generate a purified population of ESC-derived endothelial progenitor cells (EPCs) and test their potential to repair ischemia in vivo. Specifically, in Aim 1, we propose to further develop and characterize our artificial engineered niche for fundamental studies on ESC fate decisions. Aim 2 will use this system to test two competing hypotheses, namely that: 1.) ESCs can facilitate capillary morphogenesis in an indirect manner, in much the same way as adult stem cells; or 2.) ESCs can be directed down an endothelial-specific lineage by manipulating one or more instructive signals. Finally, Aim 3 will utilize our engineered niche to generate a purified population of ESC-derived EPCs and then test their ability to enhance perfusion in an animal model. Successful completion of these proposed aims may transform the clinical use of stem cells for cardiovascular disease and other ischemic pathologies by enabling identification of those factors and conditions which promote vessel formation. The versatile artificial engineered niche developed here will also yield a new tool that could enormously benefit efforts to screen the combinatorial effects of promising therapeutic compounds. Completion of the planned studies will greatly facilitate the PI’s long-term goal of developing “instructive” biomaterials and strategies to direct tissue repair.
Statement of Benefit to California: 
Human embryonic stem cells (hESCs) are pluripotent stem cells that can theoretically give rise to every cell type in the human body. Their potential use for the treatment of human diseases has been heralded with great fanfare and even some controversy. However, their therapeutic potential has yet to be realized due to an incomplete fundamental understanding of the factors that govern their differentiation. This proposal describes studies intended to assess the ability of hESCs to develop into blood vessels; in particular, capillary networks that are responsible for the delivery of oxygen and essential nutrients to all tissues in the human body. This focus is motivated by the fact that cardiovascular disease accounts for an estimated $330 billion in health care costs each year, afflicts 61.8 million Americans, and will account for more than 1.5 million deaths in the United States this year alone. It is the number one killer in this country and in California. Since many cardiovascular diseases are characterized by either insufficient blood vessel growth or damage to the existing vessels, a therapy based on hESCs could have enormous benefit to the citizens of California, the United States, and the rest of the world. Therefore, this proposal has two primary goals. First, we seek to develop a novel technology to systematically investigate the influence of multiple instructive signals on the ability of hESCs to differentiate into capillary vessels. Second, we propose to exploit knowledge gained from the basic studies using this technology to generate a purified population of hESCs and test their potential to repair ischemia (lack of blood flow) in an animal model. Successfully achieving these goals will benefit the citizens of California in three significant ways. First, our efforts may help to transform the clinical use of stem cells, not only for cardiovascular disease but other diseases as well, by enabling identification of those factors and conditions which promote hESC differentiation. Second, the versatile technology developed here will yield a powerful new tool that could enormously benefit California’s biotechnology companies in their efforts to screen the combinatorial effects of promising therapeutic compounds. Third, we expect the proposed studies to directly benefit 8-10 researchers in training and indirectly trickle down to hundreds of undergraduate students [REDACTED] enrolled in courses taught by the PI. This final benefit may perhaps have the most significant long-term economic impact by training and inspiring future leaders to pursue research and development positions in California.

Transcriptional Regulation of Cardiac Pacemaker Cell Progenitors

Funding Type: 
New Faculty I
Grant Number: 
RN1-00562
ICOC Funds Committed: 
$3 149 806
Disease Focus: 
Heart Disease
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Congenital and acquired defects of cardiac pacemakers are leading causes of morbidity and mortality in our society. Dysfunctions of the SA node and the lower conduction cells lead to a variety of complex arrhythmias that typically necessitate anti-arrhythmic therapy and implantation of devices. These treatments have significant limitations in their efficacy and risk-benefit ratio. Thus, it would be ideal to generate cell-based therapeutic approaches towards treating arrhythmias. Experimental data has provided compelling evidence that pacemaker and conduction cells of the heart separate early in development from the working myocardium and retain a relatively undifferentiated state. Prior cell-based approaches in regenerating myocardial damage in the heart have met limited success in part due to implantation of a diverse population of cells. This generally results in poor engraftment and undesirable outcomes. There is now evidence for resident conduction progenitor cells in myocardium that orchestrate the process of cell recruitment into the conduction tissue. In the current proposal we aim to identify the molecular events that lead to differentiation and formation of cardiac pacemaker cells. We will utilize the information obtained from the above experiments to generate cell based methods to treat cardiac arrhythmias. We aim to genetically manipulate the human embryonic stem cells so we can identify a selected population that is destined to become pacemaker cells. By replacing the cells responsible for normal beating of the heart, we hope to provide natural therapies for human conduction system disease
Statement of Benefit to California: 
The ultimate of goal of our proposal is identify a reliable mechanism for implementing a cell-based approach for treating human arrhythmias. Sudden cardiac death related to cardiac arrhythmia is a leading cause of morbidity and mortality in our society. The people of California have voted to implement new innovative ways of treating human disease by using human stem cells, the current project is in line with such wishes to create new therapeutic modalities towards treating heart disease.
Progress Report: 
  • Cardiovascular disease is a major source of morbidity and mortality in our society. In this case, cardiac arrhythmias are leading cause of sudden cardiac death. Therefore, it is empirical to identify the source and mechanisms of cardiac arrhythmias. The long-term objectives of our laboratory is identify the key molecules that are involved in differentiation and formation of cardiac conduction system. We utilize mouse as a model system to identify the molecular pathways leading the formation of cardiac conduction cells.
  • In the past year we have identified some of regulatory pathways that allows for the proper formation of cardiac conduction tissue. We are using mice that have specific mutations in the cells of cardiac conduction system to identify these special pathways. One such molecule that orchestrates the differentiation of cardiac conduction cells is Nkx2-5. We have determined that loss of this transcription factor is of significant detriment to the health of cardiac conduction and is the underlying factor in common arrhythmias. Our ultimate goal is to utilize the information obtained by our studies in mice, and apply them towards therapeutic functions in humans. To this end, we are trying to develop a mechanism to reprogram cardiac stem cells to behave like conduction system cells. Ultimately, this approach would be used towards stem cell therapy for cardiac arrhythmias.
  • A leading cause of heart related morbidity and mortality is cardiac rhythm disturbances. In fact sudden cardiac death is primarily due to abnormalities of cardiac electrical conduction abnormalities. At present, the therapeutic approaches to treatment of cardiac arrhythmias are limited to cardiac device including pacemakers and defibrillators. These devices are expensive and carry additional risks to the patients during after surgical implantation. Our overall goal is to identify the key regulatory pathways that lead to differentiation and formation of various cells type of cardiac conduction cells.
  • Our laboratories focuses on the molecular pathways that guide the formation of distinct cell types in the human heart. The proper formation of these cell types from a unique cardiac progenitor is an important, yet complex biological question that our laboratory is aiming to answer. In this regard, in the past year we have identified a unique molecular pathway by which a unique population of cardiac progenitor cells are added to heart and also participate in the formation and patterning of the cardiac pacemaker cells. We are using mouse models to study the formation of cardiac stem cells and also the mechanisms by which they acquire distinct identities. To this end, our mutant mouse models display abnormal formation of the SA node which is the primary site of cardiac beating. By studying the mutant mice generated by genetic manipulation of stem cells, we aim to further advance our knowledge of different forms of cardiac stem cell formation. During the past year we have made significant progress in elucidating the ways by which cardiac progenitor cells contribute the pacemaker cell formation and putting forth new paradigms for cardiac pacemaker stem cell formation.
  • Heart disease is a major cause of morbidity and mortality in our society. Congestive heart failure and cardiac arrhythmias are the most common mechanism by which heart disease leads to sudden cardiac death. Genetic studies in the general population have determined that susceptibility to cardiac arrhythmia and congestive heart failure is due to mutations in certain genes that guide cardiac development. Specifically, mutations in certain molecules called transcription factors are the leading mechanisms by which genetic defects lead to congenital heart defects and cardiac arrhythmias. Our laboratory studies the mechanism by which transcription factors and signaling molecules guide cardiac development and lead to selective formation of different cardiac cells. Our laboratory has pioneered work that has lead to the discovery of mutations that lead to cardiac arrhythmia and heart failure. In the past year, we have made steady progress in characterization of some of the key factors that guide cardiac cell development. To this end, we have identified a molecule called R-spondin-3 (Rspo3) that is critical for cardiac cell growth and probably survival. We have determined that Rspo3 functions to keep cardiac cell proliferating and loss of Rspo3 leads to thin cardiac muscle and heart failure. The mutation of Rspo3 in mouse leads to not only heart failure, but also leads to arrhythmias and valvlular heart disease. Therefore, Rspo3 functions in multiple aspect cardiac development and plays an essential role in proliferation of resident cardiac stem cells. Since, Rspo3 is known to function in a specific cardiac pathway called Wnt pathway, our hypothesis is that Rspo3 is a needed growth factor that is guiding cardiac stem cells towards growth and proliferation. We have submitted a manuscript about our work with Rspo3.
  • Our laboratory has also identified a molecule called OSR1 which plays a critical role in cardiac septation and development of conduction system. Mice that lack Osr1 have defects in atrial septation and show evidence of cardiac arrhythmias. We are in the process of submitting a manuscript that describes our results with OSR1. In summary, the generous funding by CIRM has helped us identify important new molecules with novel mechanisms critical in cardiac development.
  • Heart disease is a major cause of morbidity and mortality in our society. Congestive heart failure and cardiac arrhythmias are the most common mechanism by which heart disease leads to sudden cardiac death. Genetic studies in the general population have determined that susceptibility to cardiac arrhythmia and congestive heart failure is due to mutations in certain genes that guide cardiac development. Specifically, mutations in certain molecules called transcription factors are the leading mechanisms by which genetic defects lead to congenital heart defects and cardiac arrhythmias. Our laboratory studies the mechanism by which transcription factors and signaling molecules guide cardiac development and lead to selective formation of different cardiac cells. Our laboratory has pioneered work that has lead to the discovery of mutations that lead to cardiac arrhythmia and heart failure. In the past year, we have made steady progress in characterization of some of the key factors that guide cardiac cell development. To this end, we have identified a molecule called R-spondin-3 (Rspo3) that is critical for cardiac cell growth and probably survival. We have determined that Rspo3 functions to keep cardiac cell proliferating and loss of Rspo3 leads to thin cardiac muscle and heart failure. The mutation of Rspo3 in mouse leads to not only heart failure, but also leads to arrhythmias and valvlular heart disease. Therefore, Rspo3 functions in multiple aspect cardiac development and plays an essential role in proliferation of resident cardiac stem cells. Since, Rspo3 is known to function in a specific cardiac pathway called Wnt pathway, our hypothesis is that Rspo3 is a needed growth factor that is guiding cardiac stem cells towards growth and proliferation. We have submitted a manuscript about our work with Rspo3.
  • Our laboratory has also identified a molecule called OSR1 which plays a critical role in cardiac septation and development of conduction system. Mice that lack Osr1 have defects in atrial septation and show evidence of cardiac arrhythmias. We are in the process of submitting a manuscript that describes our results with OSR1. In summary, the generous funding by CIRM has helped us identify important new molecules with novel mechanisms critical in cardiac development.
  • The aims of the current proposal are to gain insight into the mechanisms of cardiac development as it relates to cardiac conduction system
  • and overall maturation of atria and ventricle. Our studies have identified a new key molecule that directs the maturation of cardiac cells. The secreted factor RSPO3 was found to have a significant role in the proper maturation of cardiac ventricles. We now aim to further identify the potential mechanisms by which RSPO3 Functions in the developmental maturation of the mammalian heart

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