Heart Disease

Coding Dimension ID: 
295
Coding Dimension path name: 
Heart 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.
  • 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.

Mechanism of heart regeneration by cardiosphere-derived cells

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06215
ICOC Funds Committed: 
$1 367 604
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
In the process of a heart attack, clots form suddenly on top of cholesterol-laden plaques, blocking blood flow to heart muscle. As a result, living heart tissue dies and is replaced by scar. The larger the scar, the higher the chance of premature death and disability following the heart attack. While conventional treatments aim to limit the initial injury (by promptly opening the clogged artery) and to prevent further damage (using various drugs), regenerative therapy for heart attacks seeks to regrow healthy heart muscle and to dissolve scar. To date, cell therapy with CDCs is the only intervention which has been shown to be clinically effective in regenerating the injured human heart. However, the cellular origin of the newly-formed heart muscle and the mechanisms underlying its generation remain unknown. The present grant seeks to understand those basic mechanisms in detail, relying upon state-of-the-art scientific methods and preclinical disease models. Our work to date suggests that much of the benefit is due to an indirect effect of transplanted CDCs to stimulate the proliferation of surrounding host heart cells. This represents a major, previously-unrecognized mechanism of cardiac regeneration in response to cell therapy. The proposed project will open up novel mechanistic insights which will hopefully enable us to boost the efficacy of stem cell-based treatments by bolstering the regeneration of injured heart muscle.
Statement of Benefit to California: 
Coronary artery disease is the predominant cause of premature death and disability in California. Clots form suddenly on top of cholesterol-laden plaques in the wall of a coronary artery, blocking blood flow to the heart muscle. This leads to a “heart attack”, in which living heart muscle dies and is replaced by scar. The larger the scar, the greater the chance of death and disability following the heart attack. While conventional treatments aim to limit the initial injury (by promptly opening the clogged artery) and to prevent further injury (using various drugs), regenerative therapy for heart attacks seeks to regrow healthy heart muscle and to dissolve scar. To date, cell therapy with CDCs is the only intervention that has been shown to be clinically effective in regenerating the injured human heart. However, the cellular origin of the newly-formed heart muscle and the mechanisms underlying its generation remain unknown. The present grant seeks to understand those basic mechanisms in detail, relying upon state-of-the-art scientific methods and preclinical disease models. The resulting insights will enable more rational development of novel therapeutic approaches, to the benefit of the public health of the citizens of California. Economic benefits may also accrue from licensing of new technology.
Progress Report: 
  • Key abbreviations:
  • CDCs: cardiosphere-derived cells
  • MI: myocardial infarction
  • The present award tests the hypothesis that CDCs promote regrowth of normal mammalian heart tissue through induction of adult cardiomyocyte cell cycle re-entry and proliferation (as occurs naturally in zebrafish and neonatal mice). Such a mechanism, if established, would challenge the dogma that terminally-differentiated adult cardiomyocytes cannot re-enter the cell cycle. We have employed an inducible cardiomyocyte-specific fate-mapping approach (to specifically mark resident myocytes and their progeny), coupled with novel methods of myocyte purification and rigorous quantification. We have also developed assays that enable us to exclude potential technical confounding factors. The use of bitransgenic mice is essential for our experimental design (as it enables fate mapping of resident myocytes in a mammalian model), while the use of mouse CDCs in our in vivo experiments (as opposed to human CDCs) enables us to avoid immunosuppression and its complications. To date, mouse, rat and pig models have proven to be reliable in predicting clinical effects of CDC therapy in humans, and results with human and mouse CDCs in comparable models (e.g., SCID mice for human CDCs versus wild-type mice for mouse CDCs) have not revealed any major mechanistic divergence. Our results demonstrate that induction of cardiomyocyte proliferation represents a major, previously-unrecognized mechanism of cardiac regeneration in response to cell therapy. One full-length publication describing these findings has appeared (K. Malliaras et al., EMBO Mol Med, 2013, 5:191-209), and another paper has been submitted. The work has already begun to open up novel mechanistic insights which will enable us to improve the efficacy of stem cell-based treatments and bolster cardiomyocyte repopulation of infarcted myocardium.
  • CDCs: cardiosphere-derived cells
  • MI: myocardial infarction
  • The present award tests the hypothesis that CDCs promote regrowth of normal mammalian heart tissue through induction of adult cardiomyocyte cell cycle re-entry and proliferation (as occurs naturally in zebrafish and neonatal mice). Such a mechanism, if established, would challenge the dogma that terminally-differentiated adult cardiomyocytes cannot reenter the cell cycle. We have employed an inducible cardiomyocyte-specific fate-mapping approach (to specifically mark resident myocytes and their progeny), coupled with novel methods of myocyte purification and rigorous quantification. We have also developed assays that enable us to exclude potential technical confounding factors. The use of bitransgenic mice is essential for our experimental design (as it enables fate mapping of resident myocytes in a mammalian model), while the use of mouse CDCs in our in vivo experiments (as opposed to human CDCs) enables us to avoid immunosuppression and its complications. To date, mouse, rat, and pig models have proven to be reliable in predicting clinical effects of CDC therapy in humans, and results with human and mouse CDCs in comparable models (e.g., SCID mice for human CDCs versus wild-type mice for mouse CDCs) have not revealed any major mechanistic divergence. Our results demonstrate that induction of cardiomyocyte proliferation represents a major, previously-unrecognized mechanism of cardiac regeneration in response to cell therapy. Two full-length publications describing these findings has appeared (Malliaras, K, et al., EMBO Mol Med. 2014, 6:760-777; Malliaras K, et al., EMBO Mol Med, 2013, 5:191-209). The work has already begun to open up novel mechanistic insights which will enable us to improve the efficacy of stem cell-based treatments and bolster cardiomyocyte repopulation of infarcted myocardium.

Preclinical evaluation of human embryonic stem cell-derived cardiovascular progenitors

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06378
ICOC Funds Committed: 
$2 930 388
Disease Focus: 
Heart Disease
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Because the regenerative capacity of adult heart is limited, any substantial cell loss as a result of a heart attack is mostly irreversible and may lead to progressive heart failure. Human pluripotent stem cells can be differentiated to heart cells, but their properties when transplanted into an injured heart remain unresolved. We propose to perform preclinical evaluation for transplantation of pluripotent stem cell-derived cardiac cells into the injured heart of an appropriate animal model. However, an important issue that has limited the progress to clinical use is their fate upon transplantation; that is whether they are capable of integrating into their new environment or they will function in isolation at their own pace. As an analogy, the performance of a symphony can go into chaos if one member plays in isolation from all surrounding cues. Therefore, it is important to determine if the transplanted cells can beat in harmony with the rest of the heart and if these cells will provide functional benefit to the injured heart. We plan to isolate cardiac cells derived from human pluripotent stem cells, transplant them into the model’s injured heart, determine if they result in improvement of the heart function, and perform detailed electrophysiology studies to determine their integration into the host tissue. The success of the proposed project will set the platform for future clinical trails of stem cell therapy for heart disease.
Statement of Benefit to California: 
Heart disease remains the leading cause of mortality and morbidity in the US with an estimated annual cost of over $300 billion. In California alone, more than 70,000 people die every year from cardiovascular diseases. Despite major advancement in treatments for patients with heart failure, which is mainly due to cellular loss upon myocardial injury, the mortality rate remains high. Human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC) could provide an attractive therapeutic option to treat patients with damaged heart. We propose to isolate heart cells from hESCs and transplant them in an injured animal model's heart and study their fate. In the process, we will develop reagents that can be highly valuable for future research and clinical studies. The reagents generated in these studies can be patented forming an intellectual property portfolio shared by the state and the institution where the research is carried out. Most importantly, the research that is proposed in this application could lead to future stem cell-based therapies that would restore heart function after a heart attack. We expect that California hospitals and health care entities will be first in line for trials and therapies. Thus, California will benefit economically and it will help advance novel medical care.
Progress Report: 
  • Identification and isolation of pure cardiac cells derived from human pluripotent stem cells has proven to be a difficult task. We have designed a method to genetically engineer human embryonic stem cells (hESCs) to harbor a label that is expressed during sequential maturation of cardiac cells. This will allow us to prospectively isolate cardiac cells at different stages of development for further characterization and transplantation. Using this method, we have screened proteins that are expressed on the surface of cells as markers. Using antibodies against these surface markers allows for isolation of these cells using cell sorting techniques. Thus far, we have identified two surface markers that can be used to isolate early cardiac progenitors. Using these markers, we have enriched for cardiac cells from differentiating hESCs and have characterized their properties in the dish as well as in small animals. We plan to transplant these cells in large animal models and monitor their survival, expansion and their integration into the host myocardium. Molecular imaging techniques are used to track these cells upon transplantation.

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.
  • The goal of our project is 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 two yeara. Since starting we have developed over 7 stem cell lines from patients with Danon Disease. We have used these stem cells to make heart cells and have screened hundreds of drugs on these cells. We have identified several drugs using this system that show some promise and are undergoing more rigorous testing. We have also begun working with mice that have been genetically engineered to model Danon disease. We hope that these mice can be used to test out the new drugs we have identified using our stem cell screens.

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.
Progress Report: 
  • The project objective is to design, synthesize and test a sodium-channel inhibitor analog that selectively inhibits the sodium channel and not the potassium channel in patient-derived IPSCs. The strategy is to first work out the approach with wild-type human IPSCs in advance of the patient-derived cells. The status is that the milestones for Year 1 have largely been accomplished. The achievements for this reporting period include nearly locking down the IPSC protocol, developing ultra high throughput kinetic analysis of human cardiomyocytes, developing an enantioselective synthesis of sodium-channel inhibitors and analogs and identifying from a pool of only 49 compounds, a promising sodium-channel inhibitor that provides insight into selective sodium channel inhibition.

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.
Progress Report: 
  • The California Institute for Regenerative Medicine (CIRM) Human Pluripotent Stem Cell Biorepository is operated by the Coriell Institute for Medical Research and is a critical component of the CIRM Human Stem Cell Initiative. The overall goal of this initiative is to generate, for world-wide use by non-profit and for-profit entities, high quality, disease-specific induced pluripotent stem cells (iPSCs). These cells are derived from existing tissues such as blood or skin, and are genetically manipulated in the laboratory to change into cells that resemble embryonic stem cells. iPSCs can be grown indefinitely in the Petri dish and have the remarkable capability to be converted into most of the major cell types in the body including neurons, heart cells, and liver cells. This ability makes iPSCs an exceptional resource for disease modeling as well as for drug screening. The expectation is that these cells will be a major benefit to the process for understanding prevalent, genetically complex diseases and in developing innovative therapeutics.
  • The Coriell CIRM iPSC Biorepository, located at the Buck Institute for Research on Aging in Novato, CA, is funded through a competitive grant award to Coriell from CIRM and is managed by Mr. Matt Self under the supervision of the Program Director, Dr. Steven Madore, Director of Molecular Biology at Coriell. The Biorepository will receive biospecimens consisting of peripheral blood mononuclear cells (PBMCs) and skin biopsies obtained from donors recruited by seven Tissue Collector grant awardees. These biospecimens will serve as the starting material for iPSC derivation by Cellular Dynamics, Inc (CDI). Under a contractual agreement with Coriell, CDI will expand each iPSC line to generate sufficient aliquots of high quality cryopreserved cells for distribution via the Coriell on-line catalogue. Aliquots of frozen cell lines and iPSCs will be stored in liquid nitrogen vapor in storage units at the Buck Institute with back-up aliquots stored in a safe off-site location.
  • Renovation and construction of the Biorepository began at the Buck Institute in late January. The Biorepository Manger was hired March 1 and after installation of cryogenic storage vessels and alarm validation, the first biospecimens were received on April 30, 2014. Additionally, Coriell has developed a Clinical Information Management System (CIMS) for storing all clinical and demographic data associated with enrolled subjects. Tissue Collectors utilize CIMS via a web interface to upload and edit the subject demographic and clinical information that will ultimately be made available, along with the iPSCs, via Coriell’s on-line catalogue
  • As of November 1 specimens representing a total of 725 unique individuals have been received at the Biorepository. These samples include PBMCs obtained from 550 unique individuals, skin biopsies from 72 unique individuals, and 103 primary dermal fibroblast cultures previously prepared in the laboratories of the CIRM Tissue Collectors. A total of 280 biospecimen samples have been delivered to CDI for the purpose of iPSC derivation. The Biorepository is anticipating delivery of the first batches of iPSCs for distribution in early 2015. These lines, along with the associated clinical data, will become available to scientists via the on-line Coriell catalogue. The CIRM Coriell iPSC Biorepository will ensure safe long-term storage and distribution of high quality iPSCs.

Mechanisms of Direct Cardiac Reprogramming

Funding Type: 
Basic Biology III
Grant Number: 
RB3-05174
ICOC Funds Committed: 
$1 708 560
Disease Focus: 
Heart Disease
oldStatus: 
Active
Public Abstract: 
Heart disease is a leading cause of adult and childhood mortality. The underlying pathology is typically loss of heart muscle cells that leads to heart failure, or improper development of specialized cardiac muscle cells called cardiomyocytes during embryonic development that leads to congenital heart malformations. Because cardiomyocytes have little or no regenerative capacity after birth, current therapeutic approaches are limited for the over 5 million Americans who suffer from heart failure. Embryonic stem cells possess clear potential for regenerating heart tissue, but efficiency of cardiac differentiation, risk of tumor formation, and issues of cellular rejection must be overcome. Our recent findings regarding direct reprogramming of a type of structural cell of the heart or skin called fibroblasts into cardiomyocyte-like cells using just three genes offer a potential alternative approach to achieving cardiac regeneration. The human heart is composed of muscle cells, blood vessel cells, and fibroblasts, with the fibroblasts comprising over 50% of all cardiac cells. The large population of cardiac fibroblasts that exists within the heart is a potential source of new heart muscle cells for regenerative therapy if it were possible to directly reprogram the resident fibroblasts into muscle cells. We simulated a heart attack in mice by blocking the coronary artery, and have been able to reprogram existing mouse cardiac fibroblasts after this simulated heart attack by delivering three genes into the heart. We found a significant reduction in scar size and an improvement in cardiac function that persists after injury. The reprogramming process starts quickly but is progressive over several weeks; however, how this actually occurs is unknown. Because this finding represents a new approach that could have clinical benefit, we propose to reveal the mechanism by which fibroblast cells become reprogrammed into heart muscle cells, which will be critical to refine the process for therapeutic use. We will do this by analyzing the changes in how the genome is interpreted and expressed at a genome-wide level at different time points during the process of fibroblast to muscle conversion, which represents the fundamental process that leads to reprogramming. The findings from this proposal will reveal approaches to refine and improve human cardiac reprogramming and will aid in translation of this technology for human cardiac regenerative purposes.
Statement of Benefit to California: 
This research will benefit the state of California and its citizens by helping develop a new approach to cardiac regeneration that would have a lower risk of tumor formation and cellular rejection. In addition, the approach could remove some of the hurdles of cell-based therapy including delivery challenges and incorporation challenges. The mechanisms revealed by this research will enable refinement of the method that could potentially then be used to treat the hundreds of thousands of Californians with heart failure.
Progress Report: 
  • Heart disease is a leading cause of adult and childhood mortality. The underlying pathology is typically loss of heart muscle cells that leads to heart failure, or improper development of specialized cardiac muscle cells called cardiomyocytes during embryonic development that leads to congenital heart malformations. Because cardiomyocytes have little or no regenerative capacity after birth, current therapeutic approaches are limited for the over 5 million Americans who suffer from heart failure. Embryonic stem cells possess clear potential for regenerating heart tissue, but efficiency of cardiac differentiation, risk of tumor formation, and issues of cellular rejection must be overcome.
  • Our recent findings regarding direct reprogramming of a type of structural cell of the heart or skin called fibroblasts into cardiac muscle-like cells using just three genes offer a potential route to achieve cardiac regeneration after cardiac injury. The large population of cardiac fibroblasts that exists within the heart is a potential source of new heart muscle cells for regenerative therapy if it were possible to directly reprogram the resident fibroblasts into muscle cells. In the last year, we simulated a heart attack in mice by blocking the coronary artery, and have been able to reprogram existing mouse cardiac fibroblasts after this simulated heart attack by delivering three genes into the heart. We found a significant reduction in scar size and an improvement in cardiac function that persists after injury. The reprogramming process starts quickly but is progressive over several weeks; however, how this actually occurs is unknown. Because this finding represents a new approach that could have clinical benefit, we are investigating the mechanism by which fibroblast cells become reprogrammed into heart muscle cells, which will be critical to refine the process for therapeutic use. During the last year, we have analyzed the changes in how the genome is interpreted and expressed at a genome-wide level at different time points during the process of fibroblast to muscle conversion, which represents the fundamental process that leads to reprogramming. We have also generated many reagents that will allow us to identify how the reprogramming factors interact with DNA to alter the interpretation. These reagents will be used in the coming year to more thoroughly investigate the epigenetic changes that induce changes in interpretation of the DNA, leading to the cardiac muscle phenotype. The findings from this proposal will reveal approaches to refine and improve human cardiac reprogramming and will aid in translation of this technology for human cardiac regenerative purposes.
  • Heart disease is a leading cause of adult and childhood mortality. The underlying pathology is typically loss of heart muscle cells that leads to heart failure, or improper development of specialized cardiac muscle cells called cardiomyocytes during embryonic development that leads to congenital heart malformations. Because cardiomyocytes have little or no regenerative capacity after birth, current therapeutic approaches are limited for the over 5 million Americans who suffer from heart failure. Embryonic stem cells possess clear potential for regenerating heart tissue, but efficiency of cardiac differentiation, risk of tumor formation, and issues of cellular rejection must be overcome.
  • Our recent findings regarding direct reprogramming of a type of structural cell of the heart or skin called fibroblasts into cardiac muscle-like cells using just three genes offer a potential route to achieve cardiac regeneration after cardiac injury. The large population of cardiac fibroblasts that exists within the heart is a potential source of new heart muscle cells for regenerative therapy if it were possible to directly reprogram the resident fibroblasts into muscle cells. We have simulated a heart attack in mice by blocking the coronary artery, and have been able to reprogram existing mouse cardiac fibroblasts after this simulated heart attack by delivering three genes into the heart. We found a significant reduction in scar size and an improvement in cardiac function that persists after injury. The reprogramming process starts quickly but is progressive over several weeks; however, how this actually occurs is unknown. Because this finding represents a new approach that could have clinical benefit, we are investigating the mechanism by which fibroblast cells become reprogrammed into heart muscle cells, which will be critical to refine the process for therapeutic use. During the last year, we have analyzed the changes in how the genome is interpreted and expressed at a genome-wide level at different time points during the process of fibroblast to muscle conversion, which represents the fundamental process that leads to reprogramming. We have mapped the dynamic and sequential changes that are occurring on the DNA during reprogramming of cells. In the coming year, we will be integrating data from studies of epigenetic changes, DNA-binding of reprogramming factors, and the resulting alterations in activation or repression of genes that are responsible for changing a fibroblast into a cardiac muscle cell. The findings from this proposal will reveal approaches to refine and improve human cardiac reprogramming and will aid in translation of this technology for human cardiac regenerative purposes.
  • Heart disease is a leading cause of adult and childhood mortality. The underlying pathology is typically loss of heart muscle cells that leads to heart failure, or improper development of specialized cardiac muscle cells called cardiomyocytes during embryonic development that leads to congenital heart malformations. Because cardiomyocytes have little or no regenerative capacity after birth, current therapeutic approaches are limited for the over 5 million Americans who suffer from heart failure. Embryonic stem cells possess clear potential for regenerating heart tissue, but efficiency of cardiac differentiation, risk of tumor formation, and issues of cellular rejection must be overcome.
  • Our recent findings regarding direct reprogramming of a type of structural cell of the heart or skin called fibroblasts into cardiac muscle-like cells using just three genes offer a potential route to achieve cardiac regeneration after cardiac injury. The large population of cardiac fibroblasts that exists within the heart is a potential source of new heart muscle cells for regenerative therapy if it were possible to directly reprogram the resident fibroblasts into muscle cells. We have simulated a heart attack in mice by blocking the coronary artery, and have been able to reprogram existing mouse cardiac fibroblasts after this simulated heart attack by delivering three genes into the heart. We found a significant reduction in scar size and an improvement in cardiac function that persists after injury. The reprogramming process starts quickly but is progressive over several weeks; however, how this actually occurs is unknown. Because this finding represents a new approach that could have clinical benefit, we are investigating the mechanism by which fibroblast cells become reprogrammed into heart muscle cells, which will be critical to refine the process for therapeutic use. During this project, we have analyzed the changes in how the genome is interpreted and expressed at a genome-wide level at different time points during the process of fibroblast to muscle conversion, which represents the fundamental process that leads to reprogramming. We have mapped the dynamic and sequential changes that are occurring on the DNA during reprogramming of cells. In the last year, we have determined the epigenetic changes occurring and correlated those with DNA-binding of reprogramming factors, and the resulting alterations in activation or repression of genes that are responsible for changing a fibroblast into a cardiac muscle cell. The findings from this proposal are revealing approaches to refine and improve human cardiac reprogramming and will aid in translation of this technology for human cardiac regenerative purposes.

Transcriptional Regulation of Cardiac Pacemaker Cell Progenitors

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

Tissue Collection for Accelerating iPSC Research in Cardiovascular Diseases

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

Pages

Subscribe to RSS - Heart Disease

© 2013 California Institute for Regenerative Medicine