Heart Disease

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

The CIRM Human Pluripotent Stem Cell Biorepository – A Resource for Safe Storage and Distribution of High Quality iPSCs

Funding Type: 
hPSC Repository
Grant Number: 
IR1-06600
ICOC Funds Committed: 
$9 999 834
Disease Focus: 
Developmental Disorders
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Critical to the long term success of the CIRM iPSC Initiative of generating and ensuring the availability of high quality disease-specific human IPSC lines is the establishment and successful operation of a biorepository with proven methods for quality control, safe storage and capabilities for worldwide distribution of high quality, highly-characterized iPSCs. Specifically the biorepository will be responsible for receipt, expansion, quality characterization, safe storage and distribution of human pluripotent stem cells generated by the CIRM stem cell initiative. This biobanking resource will ensure the availability of the highest quality hiPSC resources for researchers to use in disease modeling, target discovery and drug discovery and development for prevalent, genetically complex diseases.
Statement of Benefit to California: 
The generation of induced pluripotent stem cells (iPSCs) from patients and subsequently, the ability to differentiate these iPSCs into disease-relevant cell types holds great promise in facilitating the “disease-in-a-dish” approach for studying our understanding of the pathological mechanisms of human disease. iPSCs have already proven to be a useful model for several monogenic diseases such as Parkinson’s, Fragile X Syndrome, Schizophrenia, Spinal Muscular Atrophy, and inherited metabolic diseases such as 1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease. In addition, the differentiated cells obtained from iPSCs represent a renewable, disease-relevant cell model for high-throughput drug screening and toxicology/safety assessment which will ultimately lead to the successful development of new therapeutic agents. iPSCs also hold great hope for advancing the use of live cells as therapies for correcting the physiological manifestations caused by disease or injury.

Identification of Novel Therapeutics for Danon Disease Using an iPS Model of the Disease

Funding Type: 
Early Translational III
Grant Number: 
TR3-05687
ICOC Funds Committed: 
$1 701 575
Disease Focus: 
Heart Disease
Pediatrics
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Autophagy is the cells mechanism for breaking down and recycling proteins. Danon disease is an inherited disorder of autophagy. Patients with this disease have major abnormalities in heart and skeletal muscle and generally die by the time they are in their 20s. Recently we used a new technology to turn skin cells from two patients with this disease into stem cells. The objective of our work is to use these cells to find new medications. To achieve this objective we will use techniques we helped develop to make Danon disease stem cells into heart cells. We will then screen hundreds of thousands of different drugs on these heart cells, to find drugs that make these cells work better. The most promising drugs will be tested on mice with a genetic defect that is similar to those found in patients with Danon disease. When complete, the proposed research will result in the development of a drug suitable for clinical trials of patients with Danon disease. As impaired autophagy is associated with may other diseases, including heart failure, cancer and Parkinson's disease, it is possible that the drug identified will be suitable for treatment of a variety of ailments. Furthermore, the studies will serve as proof of concept for other stem cell based drug discovery systems.
Statement of Benefit to California: 
Heart failure is among the most common reasons Californians are hospitalized, and one of the greatest expenses for the health care system. Danon disease is a type of heart failure that patients inherit. It is rare but almost always fatal. Patients who suffer from Danon disease cannot correctly perform autophagy, which is a way that cells recycle proteins. We believe that our work will help in the development of new drugs to treat Danon disease. It is also possible that the drugs we discover will be useful for the treatment of other types of heart failure. As other disease such as cancer and Parkinson's disease are associated with impaired autophagy, these drugs may help them as well. From a public health perspective, the development of new drugs for heart failure would be of great benefit to Californians. Furthermore, the work could lead to additional grants from federal agency's, as well as larger studies on patients done in partnership with industry. Such studies have the potential of creating jobs and revenue for the state.
Progress Report: 
  • The goal of our project was to use stem cells to help identify new drugs for the treatment of Danon Disease, a rare, inherited disease that causes severe heart disease. Patients with Danon disease generally die in the second and third decade of life of heart failure. We have been working on this project for roughly one year. Since starting we have developed multiple stem cell lines from patients with Danon Disease. We have used these stem cells to make heart cells and have begun testing medicines on these heart cells to see if we can get them to work better. We plan in the future to identify new medicines to test any new medicines we identify on mice that have been made to mimic the disease. We are very hopeful that by the end of this project we will have come up with new ways for helping patients with this deadly disease.

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.

Building Cardiac Tissue from Stem Cells and Natural Matrices

Funding Type: 
New Faculty II
Grant Number: 
RN2-00921
ICOC Funds Committed: 
$1 706 255
Disease Focus: 
Heart Disease
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Congestive heart failure afflicts 4.8 million people, with 400,000 new cases each year. Myocardial infarction (MI), also known as a "heart attack", leads to a loss of cardiac tissue and impairment of left ventricular function. Because the heart does not contain a significant number of multiplying stem, precursor, or reserve cells, it is unable to effectively heal itself after injury and the heart tissue eventually becomes scar tissue. The subsequent changes in the workload of the heart may, if the scar is large enough, deteriorate further leading to congestive heart failure. Many stem cell strategies are being explored for the regeneration of heart tissue, however; full cardiac tissue repair will only become possible when two critical areas of tissue regeneration are addressed: 1) the generation of a sustainable, purified source of functional cardiac progenitors and 2) employment of cell delivery methods leading to functional integration with host tissue. This proposal will explore both of these 2 critical areas towards the development of a living cardiac patch material that will enable the regeneration of scarred hearts.
Statement of Benefit to California: 
The research proposed in expected to result in new techniques and methodology for the differentiation of stem cell-derived cardiomyocytes and delivery methods optimal for therapeutic repair of scarred heart tissue after a heart attack. The citizens of California could benefit from this research in three ways. The most significant impact would be in the potential potential for new medical therapies to treat a large medical problem. The second benefit is in the potential for these technologies to bring new usiness ventures to the state of California. The third benefit is the stem cell training of the students and postdocs involved in this study.
Progress Report: 
  • The proposed project aims to develop cardiac tissue for enhancing the regeneration of damaged heart. The progress in the first year involved generation of cardiac cells from stem cells, developing fabrication techniques for stem cell differentiation, and exporing cell interactions with various biodegradable materials.
  • Progress towards developing heart tissue for repairing damaged/diseaesed hearts includes stem cell differentiation towards cells that make up heart tissue and blood vessels, optimization of methods for cell expansion and cell-cell integration to generate functional tissues, and preliminary investigations of delivery materials fabrication.
  • We have optimized cardiac cell numbers from embyronic stem cells and generated a cardiac patch for delivery of these cardiac cells into damaged myocardium.
  • The aims for this study are to 1) develop methods for generating highly efficient numbers of cardiovascular cells from stem cells, and then 2) develop methods for packaging the cells into tissue-like implantable materials for repair of dead tissue following a heart attack. The final aim 3) was to examine the repair/restorative ability of the developed product in a damaged animal heart.
  • This year (4th year of the grant) was very productive. We have highly efficient methods for generating both heart (70% purity) and blood vessel cells (90% purity) and have developed a sophisticated design for packaging these into heart tissue-like materials. The animal studies are underway and initial data is promising.
  • The aim of this research proposal was to develop cardiac tissue for heart repair. Aim 1 focused on the generation of cardiac cells from stem cells. Aim 2 looks at biomaterials and patterning for building the complex multicellular integrated tissue. Aim 3 examined the ability of these tissues to repair a damaged heart. During this last year of the grant, we have successfully generate large numbers of cardiac cells from stem cells and have generated "sheets" of these cardiac cells. The animal studies on the cell injections and material injection show some success in the repair of heart tissue, but expect that the fully integrated heart tissue, once implanted, will be superior to cells or material alone.

Studying Arrhythmogenic Right Ventricular Dysplasia with patient-specific iPS cells

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06276
ICOC Funds Committed: 
$1 582 606
Disease Focus: 
Heart Disease
Pediatrics
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Most heart conditions leading to sudden death or impaired pumping heart functions in the young people (<35 years old) are the results of genetic mutations inherited from parents. It is very difficult to find curative therapy for these inherited heart diseases due to late diagnosis and lack of understanding in how genetic mutations cause these diseases. Using versatile stem cells derived from patients’ skin cells with genetic mutations in cell-cell junctional proteins, we have made a significant breakthrough and successfully modeled one of these inherited heart diseases within a few months in cell cultures. These disease-specific stem cells can give rise to heart cells, which allow us to discover novel abnormalities in heart energy consumption that causes dysfunction and death of these diseased heart cells. Currently, there is no disease-slowing therapy to these inherited heart diseases except implanting a shocking device to prevent sudden death. We propose here to generate more patient-specific stem cell lines in a dish from skin cells of patients with similar clinical presentations but with different mutations. With these new patient-specific stem cell lines, we will be able to understand more about the malfunctioned networks and elucidate common disease-causing mechanisms as well as to develop better and safer therapies for treating these diseases. We will also test our new therapeutic agents in a mouse model for their efficacy and safety before applying to human patients.
Statement of Benefit to California: 
Heart conditions leading to sudden death or impaired pumping functions in the young people (<35 years old) frequently are the results of genetic mutations inherited from parents. Currently, there is no disease-slowing therapy to these diseases. It is difficult to find curative therapy for these diseases due to late diagnosis. Many cell culture and animal models of human inherited heart diseases have been established but with significant limitation in their application to invent novel therapy for human patients. Recent progress in cellular reprogramming of skin cells to patient-specific induced pluripotent stem cells (iPSCs) enables modeling human genetic disorders in cell cultures. We have successfully modeled one of the inherited heart diseases within a few months in cell cultures using iPSCs derived from patients’ skin cells with genetic mutations in cell-cell junctional proteins. Heart cells derived from these disease-specific iPSCs enable us to discover novel disease-causing abnormalities and develop new therapeutic strategies. We plan to generate more iPSCs with the same disease to find common pathogenic pathways, identify new therapeutic strategies and conduct preclinical testing in a mouse model of this disease. Successful accomplishment of proposed research will make California the epicenter of heart disease modeling in vitro, which very likely will lead to human clinical trials and benefit its young citizens who have inherited heart diseases.
Progress Report: 
  • Most heart conditions leading to sudden death or impaired cardiac pumping functions in the young people (<35 years old) are the results of genetic mutations inherited from parents. It is very difficult to find curative therapy for these inherited heart diseases due to late diagnosis and lack of understanding in how genetic mutations cause these diseases. One of these inherited heart diseases is named arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The signature features of sick ARVD/C hearts are progressive heart muscle loss and their replacement by fat and scare tissues, which can lead to lethal irregular heart rhythms and/or heart failure. We have made a significant breakthrough and successfully modeled the sick ARVD/C heart muscles within two months in cell cultures using versatile stem cells derived from ARVD/C patients’ skin cells with genetic mutations in one of the desmosomal (a specific type of cell-cell junctions in hearts) proteins, named plakophilin-2. These disease-specific stem cells can give rise to heart cells, which allow us to discover specific abnormalities in heart energy consumption of ARVD/C heart muscles that causes dysfunction and death of these diseased heart cells. In the Year 1 of this grant support, we have made and characterized additional stem cells lines from ARVD/C patients with different desmosomal mutations. We are in the process to determine if heart muscles derived from these new ARVD/C patient-specific stem cells have common disease-causing mechanisms as we had published. We found two proposed therapeutic agents are ineffective in suppressing ARVD/C disease in culture but we have identified one potential drug that suppressed the loss of ARVD/C heart cells in culture. We also started to establish a known ARVD/C mouse model for future preclinical drug testing.

Human Embryonic Stem Cell-Derived Cardiomyocytes for Patients with End Stage Heart Failure

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05394
ICOC Funds Committed: 
$19 999 899
Disease Focus: 
Heart Disease
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Patients with end-stage heart failure have a 2-year survival rate of only 50% with conventional medical therapy. This dismal survival rate is actually significantly worse than patients with AIDS, liver cirrhosis, stroke, and other comparable debilitating diseases. Currently available therapies for end stage heart failure include drug and device therapies, as well as heart transplantation. While drug and device therapies have proven effective at reducing symptoms, hospitalizations and deaths due to heart failure, new approaches are clearly required to improve this low survival rate. Organ transplantation is highly effective at increasing patient survival, but is severely limited in its potential for broad-based application by the very low number of hearts that are available for transplantation each year. Stem cell therapy may be a promising strategy for improving heart failure patient outcomes by transplanting cells rather than a whole heart. Several studies have convincingly shown that human embryonic stem cells can be differentiated into heart muscle cells (cardiomyocytes) and that these cells can be used to improve cardiac function following a heart attack. The key objective of this CIRM Disease Team Therapy proposal is to perform the series of activities necessary to obtain FDA approval to initiate clinical testing of human embryonic stem cell-derived cardiomyocytes in end stage heart failure patients.
Statement of Benefit to California: 
Coronary artery disease (CAD) is the number one cause of mortality and morbidity in the US. The American Heart Association has estimated that 5.7 million Americans currently suffer from heart failure, and that another 670,000 patients develop this disease annually. Cardiovascular disease has been estimated to result in an estimated $286 billion in direct and indirect costs in the US annually (NHLBI, 2010). As the most populous state in the nation, California bears a substantial fraction of the social and economic costs of this devastating disease. In recent years, stem cell therapy has emerged as a promising candidate for treating ischemic heart disease. Research by our group and others has demonstrated that human embryonic stem cells (hESCs) can be differentiated to cardiomyocytes using robust, scalable, and cGMP-compliant manufacturing processes, and that hESC-derived cardiomyocytes (hESC-CMs) can improve cardiac function in relevant preclinical animal models. In this proposal, we seek to perform the series of manufacturing, product characterization, nonclinical testing, clinical protocol development, and regulatory activities necessary to enable filing of an IND for hESC-CMs within four years. These IND development activities will be in support of a Phase 1 clinical trial to test hESC-CMs in heart failure patients for the first time. If successful, this program will both pave the way for a promising new therapy to treat Californians with heart failure numbering in the hundreds of thousands, and will further enhance California’s continuing prominence as a leader in the promising field of stem cell research and therapeutics.
Progress Report: 
  • Patients with end-stage heart failure (ESHF), which can result from heart attacks, have a 2-year survival rate of 50% with conventional medical therapy. Unlike cells of other organs, the billions of cardiomyocytes lost due to damage or disease do not regenerate. Recently, implantable mechanical pumps that take over the function of the failing left ventricle (left ventricular assist devices; LVADs) have been used to prolong the lives of heart failure patients. However, these devices carry an increased risk of stroke. The only current bona fide cure for ESHF is heart transplantation, but the shortage of donor organs and the risks associated with life-long use of powerful immunosuppressive drugs limit the number of patients that can be helped.
  • Human embryonic stem cells (hESCs) have the unique properties of being able to grow without limit and to be converted into all the cell types of the body, including cardiomyocytes. Our project seeks to find ways to treat patients by replacing their lost cardiomyocytes with healthy ones derived from hESC. The ultimate goal of this 4 year project is to evaluate the feasibility, safety, and efficacy of this approach in both small and large animal models of heart disease and to use this data to initiate a clinical trial to test the therapy in patients.
  • In our first year, we developed methods for producing essentially unlimited quantities of cardiomyocytes from hESCs using a process that is compatible both with clinical needs and large-scale industrial cell production. We have also developed models of heart disease in both rats and pigs, and have begun transplanting the stem cell-derived cardiomyocytes into the rat model. We have demonstrated that stem cell-derived cardiomyocytes can engraft in this animal model and we are testing their effects on the pumping function of the heart, the growth of replacement blood vessels lost during a heart attack, and the size of the scar that typically forms after injury. In the next several years, we will continue to evaluate the safety and function of these cells and will start to transplant in our large animal model of heart disease, which will enable us to test these cells in a heart with very similar characteristics to humans, delivered in a minimally invasive way that would be ideal for clinical use.

Allogeneic Cardiac-Derived Stem Cells for Patients Following a Myocardial Infarction

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05735
ICOC Funds Committed: 
$19 782 136
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
The proposed research will demonstrate both safety and efficacy of a heart-derived stem cell product in patients who have experienced a heart attack either recently or in the past by conducting a mid-stage clinical trial. A prior early-stage trial showed that the product can repair damaged portions of the heart after a heart attack in ways that no commercial therapy currently can. Damaged areas turn irreversibly into scar tissue after the initial event, which can predispose a person to future events and lead to an ongoing worsening of general and heart health. Data from the early-stage trial suggest that treatment with the heart-derived cell product under development can turn scar tissue back into healthy heart muscle. The planned mid-stage trial will hopefully confirm that finding in a larger patient group and provide additional data to support the safety profile of the product. The product is manufactured using heart tissue obtained from a healthy donor and can be used in most other individuals. Its effect is thought to be long-lasting (months-years) although it is expected to be cleared from the body relatively quickly (weeks-months). Treatment is administered during a single brief procedure, requiring a local anesthetic and insertion of a tube (or catheter) into the heart. The overriding goal for the product is to prevent patients who have had a heart attack from deteriorating over time and developing heart failure, a condition which is defined by the heart’s inability to pump blood efficiently and one which affects millions of Americans. Successful completion of the proposed mid-stage trial would lead next to a final, confirmatory trial and then to the application process by which permission to market the product is obtained from the Food and Drug Administration. The end result could be an affordable stem cell therapy effective as part of a treatment regimen after a heart attack.
Statement of Benefit to California: 
The manufacturer of the heart-derived stem cell product under development is a California-based small company who currently employs 7 California residents. Five new local jobs will be created to support the proposed project. Three medical centers located in California will participate in the proposed mid-stage clinical trial. The trial will hopefully bring notoriety to both the company and the medical centers involved while at the same time provide a novel therapeutic option for the many citizens of California afflicted with heart disease. Recent statistics place California among the 50% of states with the highest death rates for heart disease. Therefore, a successfully developed cell product could have a meaningful impact on the home population. Furthermore, as manufacturing needs grow to accommodate the demands of early commercialization, the company anticipates generating 100+ new biotech jobs.
Progress Report: 
  • This project aims to demonstrate both safety and efficacy of a heart-derived cell product in patients who have experienced a heart attack either recently or in the past by conducting a mid-stage (Phase II) clinical trial. The cell product is manufactured using heart tissue obtained from a healthy donor and can be used in most other individuals. Its effect is thought to be long-lasting (months-years) although it is expected to be cleared from the body relatively quickly (weeks-months). Treatment is administered during a single brief procedure, requiring a local anesthetic and insertion of a tube (or catheter) into the heart. The overriding goal for the product is to prevent patients who have had a heart attack from deteriorating over time and developing heart failure, a condition which is defined by the heart’s inability to pump blood efficiently and one which affects millions of Americans. At the outset of the project, a Phase I trial was underway. By the close of the current reporting period, the Phase 1 trial had reached its main safety endpoint, and the Phase II trial was approved to proceed. Fourteen patients were treated with the heart-derived cell product as part of Phase I. The safety endpoint for the trial was pre-defined and took into consideration the following: inflammation in the heart accompanied by an immune response, death due to abnormal heart rhythms, sudden death, repeat heart attack, treatment for symptoms of heart failure, need for a heart assist device, and need for a heart transplant. Both an independent Data and Safety Monitoring Board (DSMB) and CIRM agreed that Phase I met its safety endpoint and that Phase II was approved to proceed. The Phase I participants continue to be monitored for safety and efficacy. Meanwhile, the manufacturing processes established to create cell products for use in Phase I, were employed to create cell products in anticipation of Phase II. A supply of products was readied for use in Phase II. Also in anticipation of Phase II, a number of clinical sites were readied for participation. Manufacturing data and trial status updates were also provided to the Food and Drug Administration (FDA).

Elucidating Molecular Basis of Hypertrophic Cardiomyopathy with Human Induced Pluripotent Stem Cells

Funding Type: 
Basic Biology III
Grant Number: 
RB3-05129
Investigator: 
ICOC Funds Committed: 
$1 425 600
Disease Focus: 
Heart Disease
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Familial hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young people, including trained athletes, and is the most common inherited heart defect. Until now, studies in humans with HCM have been limited by a variety of factors, including variable environmental stimuli which may differ between individuals (e.g., diet, exercise, and lifestyle), the relative difficulty in obtaining human cardiac samples, and inadequate methods of maintaining human heart tissue in cell culture systems. Cellular reprogramming methods that enable derivation of human induced pluripotent stem cells (hiPSCs) from adult cells, which can then be differentiated into cardiomyocytes (hiPSC-CMs), are a revolutionary tool for creating disease-specific cell lines that may lead to effective targeted therapies. In this proposal, we will derive hiPSC-CMs from patients with HCM and healthy controls, then perform a battery of functional and molecular tests to determine the presence of cardiomyopathic disease and associated abnormal molecular programs. With these preliminary studies, we believe hiPSC-CMs with HCM phenotype will dramatically enhance the ability to perform future high-throughput drug screens, evaluate gene and cell therapies, and assess novel electrophysiologic interventions for potential new therapies of HCM. Because HCM is not a rare disease but rather the leading cause of inherited heart defects, we believe the findings here should have broad clinical and scientific impact toward understanding the molecular and cellular basis of HCM.
Statement of Benefit to California: 
Familial hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young people and is the most common inherited heart defect. In this study, we will generate hiPSC-derived cardiomyocytes from patients with HCM, then perform a number of functional, molecular, bioinformatic, and imaging analyses to determine the extent and nature of cardiomyopathic disease. We believe hiPSC-CMs with HCM phenotype will dramatically enhance the ability to perform future high-throughput drug screens, evaluate gene and cell therapies, and assess electrophysiologic interventions for potential novel therapies of HCM. The experiments outlined are pertinent and central to the overall mission of CIRM, which seeks to explore the use of stem cell platforms to yield novel mechanistic insights into the molecular and cellular basis of disease. Because HCM is not an orphan disease, but rather the leading cause of sudden cardiac death in young people, we believe the research findings will benefit the state of California and its citizens.
Progress Report: 
  • Familial hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young people, including trained athletes, and is the most common inherited heart defect. In this proposal, we will generate human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from patients with HCM. The specific aims are as follow:
  • Specific Aim 1: Generate iPSCs from patients with HCM and healthy controls.
  • Specific Aim 2: Determine the extent of disease by performing molecular and functional analyses of hiPSC-CMs.
  • Specific Aim 3: Rescue the molecular and functional phenotypes using zinc finger nuclease (ZFN) technology.
  • Over the past year, we have now derived iPSCs from a 10-patient family cohort with the MYH7 mutation. Established iPSC lines from all subjects were differentiated into cardiomyocyte lineages (iPSC-CMs) using standard 3D EB differentiation protocols. We found hypertrophic iPSC-CMs exhibited features of HCM such as cellular enlargement and multi-nucleation beginning in the sixth week following induction of cardiac differentiation. We also found hypertrophic iPSC-CMs demonstrated other hallmarks of HCM including expression of atrial natriuretic factor (ANF), elevation of β-myosin/α-myosin ratio, calcineurin activation, and nuclear translocation of nuclear factor of activated T-cells (NFAT) as detected by immunostaining. Blockade of calcineurin-NFAT interaction in HCM iPSC-CMs by cyclosporin A (CsA) and FK506 reduced hypertrophy by over 40%. In the absence of inhibition, NFAT-activated mediators of hypertrophy such as GATA4 and MEF2C were found to be significantly upregulated in HCM iPSC-CMs beginning day 40 post-induction of cardiac differentiation, but not prior to this point. Taken together, these results indicate that calcineurin-NFAT signaling plays a central role in the development of the HCM phenotype as caused by the Arg663His mutation.
  • Familial hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young people, including trained athletes, and is the most common
  • inherited heart defect. In this proposal, we will generate and characterize human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from patients with HCM. The
  • specific aims are as follow:
  • Specific Aim 1: Generate iPSCs from patients with HCM and healthy controls.
  • Specific Aim 2: Determine the extent of disease by performing molecular and functional analyses of hiPSC-CMs.
  • Specific Aim 3: Rescue the molecular and functional phenotypes using zinc finger nuclease (ZFN) technology.
  • Over the past year, we have characterized the pathological phenotypes from iPSCs derived from a 10-patient family cohort with the MYH7 mutation.
  • We've differentiated all stablished iPSC lines from all subjects into cardiomyocyte using a modified protocol from that published by Palacek in PNAS 2011. This protocol increased the yield of cardiomyocytes significantly to consistently greater than 70% beating cardiomyocytes. We then tested the electrophysiological properties of iPSC-CMs from control and patients with HCM and found that both control and patient iPSC-CM display atrial, ventricular and nodal-like electrical waveforms by whole cell patch clamping. However, by day 30, a large subfraction (~40%) of the HCM iPSC-CM exhibit arrhythmic waveforms including delayed after-depolarizations (DADs) compared with control (~5.1%). In addition we found that treatment of HCM hiPSC-CM with positive inotropic agents (beta-adrenergic agonist - isoproterenal) for 5 days caused an earlier increase in cell size by 1.7 fold as compared to controls and significant increase in irregular calcium transients. Furthermore, we found that HCM iPSC-CMs exhibited frequent arrhythmia due to their increased intracellular calcium level by 30% at baseline. These HCM iPSC-CM also exhibited decreased calcium release by the sarcoplasmic reticulum. These findings emphasize the role of irregular calcium recycling in the pathogenesis of HCM. To confirm that the regulation of myocyte calcium is the key to HCM pathogenesis, we treated several lines from multiple HCM patients with calcium channel blocker (verapamil/diltiazem) and found that this treatment significantly ameliorated all aspects of the HCM phenotype including myocyte hypertrophy, calcium handling abnormalities, and arrhythmia. These finding supports the use of calcium channel blockers in patients with HCM and encourages further clinical studies in HCM patients using these agents.

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.

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.

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