Heart Disease

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

Center of Excellence for Stem Cell Genomics

Funding Type: 
Genomics Centers of Excellence Awards (R)
Grant Number: 
GC1R-06673-A
ICOC Funds Committed: 
$40 000 000
Disease Focus: 
Brain Cancer
Cancer
Developmental Disorders
Heart Disease
Cancer
Genetic Disorder
Stem Cell Use: 
iPS Cell
Embryonic Stem Cell
Adult Stem Cell
Cancer Stem Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 
The Center of Excellence in Stem Cell Genomics will bring together investigators from seven major California research institutions to bridge two fields – genomics and pluripotent stem cell research. The projects will combine the strengths of the center team members, each of whom is a leader in one or both fields. The program directors have significant prior experience managing large-scale federally-funded genomics research programs, and have published many high impact papers on human stem cell genomics. The lead investigators for the center-initiated projects are expert in genomics, hESC and iPSC derivation and differentiation, and bioinformatics. They will be joined by leaders in stem cell biology, cancer, epigenetics and computational systems analysis. Projects 1-3 will use multi-level genomics approaches to study stem cell derivation and differentiation in heart, tumors and the nervous system, with implications for understanding disease processes in cancer, diabetes, and cardiac and mental health. Project 4 will develop novel tools for computational systems and network analysis of stem cell genome function. A state-of-the-art data management program is also proposed. This research program will lead the way toward development of the safe use of stem cells in regenerative medicine. Finally, Center resources will be made available to researchers throughout the State of California through a peer-reviewed collaborative research program.
Statement of Benefit to California: 
Our Center of Excellence for Stem Cell Genomics will help California maintain its position at the cutting edge of Stem Cell research and greatly benefit California in many ways. First, diseases such as cardiovascular disease, cancer, neurological diseases, etc., pose a great financial burden to the State. Using advanced genomic technologies we will learn how stem cells change with growth and differentiation in culture and can best be handled for their safe use for therapy in humans. Second, through the collaborative research program, the center will provide genomics services to investigators throughout the State who are studying stem cells with a goal of understanding and treating specific diseases, thereby advancing treatments. Third, it will employ a large number of “high tech” individuals, thereby bringing high quality jobs to the state. Fourth, since many investigators in this center have experience in founding successful biotech companies it is likely to “spin off” new companies in this rapidly growing high tech field. Fifth, we believe that the iPS and information resources generated by this project will have significant value to science and industry and be valuable for the development of new therapies. Overall, the center activities will create a game-changing network effect for the state, propelling technology development, biological discovery and disease treatment in the field.

Improving Existing Drugs for Long QT Syndrome type 3 (LQT3) by hiPSC Disease-in-Dish Model

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06857
ICOC Funds Committed: 
$6 361 618
Disease Focus: 
Heart Disease
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
This project uses patient hiPSC-derived cardiomyocytes to develop a safe and effective drug to treat a serious heart health condition. This research and product development will provide a novel method for a human genetic heart disorder characterized by long delay (long Q-T interval) between heart beats caused by mutations in the Na+ channel α subunit. Certain patients are genetically predisposed to a potentially fatal arrhythmogenic response to existing drugs to treat LQT3 since the drugs have off-target effects on other important ion channels in cardiomyocytes. We will use patient-derived hiPSC-cardiomyocytes to develop a safer drug (development candidate, DC) that will retain efficacy against the "leaky" Na+-channel yet minimize off-target effects in particular against the K+ hERG channel that can be responsible for the existing drug’s pro-arrhythmic effect. Since this problem is thought to occur severely in patients with the common KCHN2 variant, K897T (~33% of the white population), removing the off-target liability addresses a serious unmet clinical need. Futher, since we propose to modify an existing drug (i.e., do drug rescue), the path from patient-specific hiPSCs to clinic might be easier than for a completely new chemical entity. Lastly, an appealing aspect is that the hiPSCs were derived from a child to test his therapy, & we aim to produce a better drug for his treatment. Our goal is to complete development of the DC and initiate IND-enabling in vivo studies.
Statement of Benefit to California: 
In the US, an estimated 850,000 adults are hospitalized for arrhythmias each year, making arrhythmias one of the top five causes of healthcare expenditures in the US with a direct cost of more than $40 billion annually for diagnosis, treatment & rehabilitation. The State of California has approximately 12% of the US population which translates to 102,000 individuals hospitalized every year for arrhythmias. Another 30,000 Californians die of sudden arrhythmic death syndrome every year. Arrhythmias are very common in older adults and because the population of California is aging, research to address this issue is important for human health and the State economy. Most serious arrhythmias affect people older than 60. This is because older adults are more likely to have heart disease & other health problems that can lead to arrhythmias. Older adults also tend to be more sensitive to the side effects of medicines, some of which can cause arrhythmias. Some medicines used to treat arrhythmias can even cause arrhythmias as a side effect. In the US, atrial fibrillation (a common type of arrhythmia that can cause problems) affects millions of people & the number is rising. Accordingly, the same problem is present in California. Thus, successful completion of this work will not only provide citizens of California much needed advances in cardiovascular health technology & improvement in health care but an improved heart drug. This will provide high paying jobs & significant tax revenue.

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.

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).

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.

Transcriptional Regulation of Cardiac Pacemaker Cell Progenitors

Funding Type: 
New Faculty I
Grant Number: 
RN1-00562
ICOC Funds Committed: 
$2 974 806
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.

Embryonic Stem Cell-Derived Therapies Targeting Cardiac Ischemic Disease

Funding Type: 
Comprehensive Grant
Grant Number: 
RC1-00124
ICOC Funds Committed: 
$2 524 617
Disease Focus: 
Heart Disease
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Cardiovascular disease (CVD) is the leading cause of death in the United States. Over one million Americans will suffer from a new or recurrent heart attacks this year and over 40 percent of those will die suddenly. In addition, about two-thirds of the patients develop congestive heart failure; and in people diagnosed with CHF, sudden cardiac death occurs at 6-9 times the general population rate. Heart transplantation remains the only viable solution for severely injured hearts; however, this treatment is limited by the availability of donor hearts. Therefore, alternative strategies to treat end stage heart failure and blocked blood vessels are needed. The objective of this proposal is to determine whether human embryonic stem (hES) cell can be used for repairing the heart. Our collaborator Advanced Cell Technology (ACT) has recently succeeded in identifying conditions for the reproducible isolation of hES cells which have the characteristics of cells which form blood vessels and heart muscle. This proposal will assess whether the hES cells can form new functional blood vessels and repair injured heart muscle in a rat model of heart attacks. Results from these studies will help develop new therapies for treating patients with heart attacks.
Statement of Benefit to California: 
Cardiovascular disease (CVD) is the leading cause of death in California and the United States. Over one million Americans will suffer from a new or recurrent myocardial infarction this year and over 40 percent of those will die suddenly. In addition, about two-thirds of myocardial infarction patients develop congestive heart failure. The 5-year mortality rate for CHF is about 50%, and in people diagnosed with CHF, sudden cardiac death occurs at 6-9 times the general population rate. Heart transplantation remains the only viable solution for severely injured hearts; however, this treatment is limited by the availability of donor hearts. It is estimated that health care costs for CVD is over 18 billion dollars a year. Additionally, the morbidity associated with CVD cost California and the nation billions of dollars a year. Therefore, alternative strategies to treat end stage heart failure and ischemia are needed. (Source: American Heart Association. Heart Disease and Stroke Facts, 2004, Dallas, TX: AHA 2004; American Heart Association. Heart Disease and Stroke Statistics-2006 Update, Dallas, TX: AHA 2006). The field of regenerative medicine is important to California and the nation. Advances in the technology to find cell based therapies will be revolutionary in their impact on patient care. Human embryonic stem (hES) cells have the potential to become all of the cells in the human body, and their unique properties give researchers the hope that from these primitive cells new therapies can result that may be available in time for the looming health care crisis. This project is focused on a pre-clinical application of a specific hES cell based therapy for myocardial regeneration and an antibody targeting technology to direct stem cells to injured organs. This project will benefit California in several ways including: 1) support for UC trainees, 2) potential of developing important clinical trials in CA based on results from this proposal, and 3) enhancement of the biotechnology industry in CA which would lead to the creation of new jobs in CA and an enhanced tax base.
Progress Report: 
  • Myocardial infarction can lead to death and disability with a 5-year death rate for congestive heart failure of 50%. It is estimated that cardiovascular disease is the leading cause of mortality and morbidity and is predicted to be the leading cause of death worldwide by 2020. Currently, heart transplantation is the only successful treatment for end-stage heart failure; however, the ability to provide this treatment is limited by the availability of donor hearts. Therefore, alternative therapies for both acute and chronic myocardial ischemia need to be developed.
  • Our results demonstrate that human embryonic stem cell (hESC)-derived hemangioblasts can create new blood vessels and improve blood flow in a rodent model of myocardial infarction. We demonstrated that adult stem cells (bone marrow CD34+ cells) can be successfully targeted to injured heart tissue, thus avoiding surgery or invasive catheter based therapies. The antibody technology can be used to target hESC-derived hemangioblasts specifically to injured heart tissue.
  • Further studies are needed to confirm our initial findings, determine whether the new blood vessel formation lead to an increase in heart function and safety studies. Studies are in progress to improve the efficiency and effectiveness of hESC-derived hemangioblasts to create new blood vessels. Additionally, investigations are underway to determine if immunosuppressive drugs will be necessary to increase survival of the hESC-derived hemangioblast. Our initial finding of hES-derived hemangioblasts inducing new blood vessel formation may eventually lead to the development of an unlimited and reliable cell source for renewing blood vessels and treating myocardial infarction.
  • Coronary artery disease (CAD) remains the leading cause of morbidity and mortality worldwide and is predicted to be the leading cause of death by 2020. In the US, it is estimated that cardiovascular disease affects 60 million patients costing the healthcare system approximately $186 billion annually. Approximately two-thirds of patients sustaining a myocardial infarction do not make a complete recovery and often are left with debilitating congestive heart failure. Despite the advances in medical treatment and interventional procedures to reduce mortality in patients with CAD, the number of patients with refractory myocardial ischemia and congestive heart failure is rapidly increasing. For end-stage heart failure, heart transplantation is the only successful treatment. However, the ability to provide this treatment is limited by the availability of donor hearts. Therefore, alternative therapies in the prevention and treatment of end-stage heart failure are needed.
  • Critical to any heart repair strategy is the need to provide vessels to allow for an adequate blood supply to nourish the heart. Our results demonstrate that human embryonic stem cell (hESC)-derived hemangioblasts can create new blood vessels and improve blood flow in a rodent model of myocardial infarction. Studies are in progress to improve the efficiency and effectiveness of hESC-derived hemangioblasts to create new blood vessels. Strategies to improve efficiency and effectiveness include the use of extracellular matrix proteins (components that make up the structural aspect of the heart) to increase the survival of the cells or the use of antibodies to direct and link the cells to the damaged heart muscle. Additionally, to decrease the risk of tumor formation from the hESC-derived hemangioblasts, the hESC-derived hemangioblasts are being cultured to form more mature endothelial cells (cells that mimic the bodies natural cells that produce blood vessels). These cells are being tested to determine whether they can effectively induce blood vessels in the heart. Our initial finding of hES-derived hemangioblasts inducing new blood vessel formation may eventually lead to the development of an unlimited and reliable cell source for renewing blood vessels and treating myocardial infarction.
  • Coronary artery disease (CAD) remains the leading cause of morbidity and mortality worldwide and is predicted to be the leading cause of death by 2020. In the US, it is estimated that cardiovascular disease affects 60 million patients costing the healthcare system approximately $186 billion annually. Approximately two-thirds of patients sustaining a myocardial infarction do not make a complete recovery and often are left with debilitating congestive heart failure. Despite the advances in medical treatment and interventional procedures to reduce mortality in patients with CAD, the number of patients with refractory myocardial ischemia and congestive heart failure is rapidly increasing. For end-stage heart failure, heart transplantation is the only successful treatment. However, the ability to provide this treatment is limited by the availability of donor hearts. Therefore, alternative therapies in the prevention and treatment of end-stage heart failure are needed.
  • Critical to any heart repair strategy is the need to provide vessels to allow for an adequate blood supply to nourish the heart. Our results demonstrate that human embryonic stem cell (hESC)-derived hemangioblasts can create new blood vessels and improve blood flow in a rodent model of myocardial infarction. Subsequent studies with hESC-derived endothelial progenitor cells decreased MI size and improved LV function in a mouse model of myocardial ischemia. Studies are in progress to improve the efficiency and effectiveness of hESC-derived endothelial progenitor cells to create new blood vessels.
  • Strategies to improve efficiency and effectiveness of stem cell therapy include the use of extracellular matrix proteins (components that make up the structural aspect of the heart) to increase the survival of the cells or the use of antibodies to direct and link the cells to the damaged heart muscle. We have demonstrated that antibodies can direct stem cells to injured myocardial tissue. Continued studies are in progress to perform studies needed for the submission of an IND. The development of peptide-modified scaffolds for the treatment of chronic heart failure has produced initial proof of concept studies that a tissue engineering approach for restoration of an injured heart is possible. Additionally, we have demonstrated that extracellular matrix derived peptides can recruit endogenous cardiac stem cells. Further development of a biopolymer scaffold for the treatment of chronic heart failure is in progress.
  • Coronary artery disease (CAD) remains the leading cause of morbidity and mortality worldwide and is predicted to be the leading cause of death by 2020. In the US, it is estimated that cardiovascular disease affects 60 million patients costing the healthcare system approximately $186 billion annually. Approximately two-thirds of patients sustaining a myocardial infarction do not make a complete recovery and often are left with debilitating congestive heart failure. Despite the advances in medical treatment and interventional procedures to reduce mortality in patients with CAD, the number of patients with refractory myocardial ischemia and congestive heart failure is rapidly increasing. For end-stage heart failure, heart transplantation is the only successful treatment. However, the ability to provide this treatment is limited by the availability of donor hearts. Therefore, alternative therapies in the prevention and treatment of end-stage heart failure are needed.
  • Critical to any heart repair strategy is the need to provide vessels to allow for an adequate blood supply to nourish the heart. Our results demonstrate that human embryonic stem cell (hESC)-derived hemangioblasts can create new blood vessels and improve blood flow in a rodent model of myocardial infarction. Subsequent studies with hESC-derived endothelial progenitor cells decreased MI size and improved LV function in a mouse model of myocardial ischemia. Studies are in progress to improve the efficiency and effectiveness of hESC-derived endothelial progenitor cells to create new blood vessels.
  • Strategies to improve efficiency and effectiveness of stem cell therapy include the use of extracellular matrix proteins (components that make up the structural aspect of the heart) to increase the survival of the cells or the use of antibodies to direct and link the cells to the damaged heart muscle. We have demonstrated that antibodies can direct stem cells to injured myocardial tissue. Continued studies are in progress to perform studies needed for the submission of an IND. The development of peptide-modified scaffolds for the treatment of chronic heart failure has produced initial proof of concept studies that a tissue engineering approach for restoration of an injured heart is possible. Additionally, we have demonstrated that extracellular matrix derived peptides can recruit endogenous cardiac stem cells. Further development of a biopolymer scaffold for the treatment of chronic heart failure is in progress.

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.

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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