Heart Disease

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

Human Cardiovascular Progenitors, their Niches and Control of Self-renewal and Cell Fate

Funding Type: 
Basic Biology I
Grant Number: 
RB1-01354
ICOC Funds Committed: 
$1 378 076
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Closed
Public Abstract: 
For the millions of Americans who are born with or develop heart disease, stem cell research offers the first hope of reversing or repairing heart muscle damage. Thus, early reports suggesting heart regeneration after transplantation of adult bone marrow-derived stem cells were met with great excitement in both the scientific and lay community. However, although adult stem cell transplantation was shown to be safe, results from over a dozen clinical trials concluded that the benefits were modest at best and whether any true regeneration is occurring was questionable. The basis for these disappointing results may be related to poorly characterized cell types used that have little capacity for true regeneration and an inadequate understanding the factors necessary for survival and differentiation of transplanted stem cells. In this application, we are proposing to study the growth and differentiation properties of an authentic endogenous human cardiac progenitor cell that can differentiate into cardiac muscle cells, smooth muscle cells and endothelial cells. We will also determine the factors that support its growth and renewal during normal development. This knowledge will be applied to future clinical trials of cardiovascular cell therapy that allow truly regenerative therapy.
Statement of Benefit to California: 
Heart disease, stroke and other cardiovascular diseases are the #1 killer in California. Despite medical advances, heart disease remains a leading cause of disability and death. Recent estimates of its cost to the U.S. healthcare system amounts to almost $300 billion dollars. Although current therapies slow the progression of heart disease, there are few, if any options, to reverse or repair damage. Thus, regenerative therapies that restore normal heart function would have an enormous societal and financial impact not only on Californians, but the U.S. more generally. The research that is proposed in this application could lead to new therapies that would restore heart function after and heart attack and prevent the development of heart failure and death.
Progress Report: 
  • In this application, we propose to study the growth and differentiation properties of an authentic endogenous human cardiac progenitor cells (CPCs) that can differentiate into cardiac muscle cells, smooth muscle cells and endothelial cells. We have isolated these multipotent CPCs from human ventricles and human induced pluripotent cells and compared therie differentiation potential. Additionally, we have characterized a cardiac niche in the developing heart, demonstrated that both the extracellulat matrix molecules and the three dimensional environment is important for CPC renewal. We believe these experiments will significantly advance out understanding of the biology of CPCs and facilitate their application as a regenerative therapy.
  • In this application, we propose to study the growth and differentiation properties of an authentic endogenous human cardiac progenitor cells (CPCs) that can differentiate into cardiac muscle cells, smooth muscle cells and endothelial cells. We have isolated these multipotent CPCs from human ventricles and human induced pluripotent cells and compared therie differentiation potential. Additionally, we have characterized a cardiac niche in the developing heart, demonstrated that both the extracellulat matrix molecules and the three dimensional environment is important for CPC
  • renewal. We believe these experiments will significantly advance out understanding of the biology of CPCs and facilitate their application as a regenerative therapy.

Detection of Cell Lineages Among Stem Cell Progeny by microRNA Profiling

Funding Type: 
SEED Grant
Grant Number: 
RS1-00239-A
ICOC Funds Committed: 
$0
Disease Focus: 
Heart Disease
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Many currently untreatable degenerative diseases are caused by the loss or dysfunction of cells in the body. Human embryonic stem (hES) cells are the first type of human cell cultured in the laboratory that have the potential to become any of the several hundred cell types in the developing human. The goal, therefore, of regenerative medicine is to develop the means of transforming hES cells into populations of cells that can be used to restore function in tissues lost as a result of disease. A critical milestone in the path from the lab bench to the hospital bedside is the development of techniques for manufacturing protocols to reliably obtain pure populations of desired cell types (in some cases relatively rare cell types). Some of the central regulators of cell fate (that is, whether hES cells become lung, heart, or brain) are known such as the “homeodomain” proteins. It is well-established that the homeodomain proteins are central regulators in the construction of the body plan, but no one has described an efficient means of influencing these regulatory proteins to makes cells of interest from hES cells. The recent discovery of a new class of RNA molecules called microRNAs (miRNAs) is stimulating a great deal of interest in the scientific community because these molecules appear to play a master regulatory role over many of the genes in the cell including some of the homeodomain proteins. However, because of profound differences between species, data being obtained in mice is not predictive of how these RNAs govern human cell fate decisions. Therefore medical research would benefit from a method to define how these molecules control hES cell differentiation. The aim of this grant is to accomplish a comprehensive profling of these miRNAs during hES cell differentiation in vitro. We have developed a new method of sorting out the many kinds of cells that originate from hES cells. We will utilize this bank of 100+ diverse hES-derived clonal differentiated cell lines each of which has a complete gene expression profile. We will obtain a large-scale miRNA profile for representative members of these purified cell types and then, using mathematical methods, we will identify the potential master regulatory genes that these miRNAs target. Lastly, we anticipate that our experimental system will allow us to then test these miRNAs to determine whether our hypothesis is actually correct and whether we can use these master regulatory molecules to steer hES cells into the lineages most needed in medicine, including those useful in the discovery of new drugs, and for human therapy to restore function in a broad array of diseases where the the loss or dysfunction of cells is the cause of the disease.
Statement of Benefit to California: 
California, like much of the United States, is facing a staggering challenge to its health care system. The large investments made in recent decades by the National Institutes of Health (NIH) have largely ignored the problems of age-related degenerative disease. As a result, increasingly physicians are treating the chronic, debilitating, and therefore expensive diseases associated with aging. This is made all the worse by the demographic wave caused by the entry of the Baby Boomers into retirement. It is estimated that by the year 2010, the Baby Boomers will be 25 percent of the population of California. By 2020 they will be approaching 64 years of age. As a result, the percentage of the elderly in California is expected to grow from 14 percent in 1990 to 22 percent in 2030. (Source: California Department of Finance, Population Projections 1993). Many of the chronic devastating diseases of an aging population are the degenerative diseases. Generally speaking, degenerative diseases are those diseases caused by the loss or dysfunction of cells. Examples include osteoarthritis (loss of cartilage cells that protect the ends of the bones), Parkinson’s disease (the loss of dopminergic neurons), osteoporosis (dysfunction of osteoblasts), macular degeneration (dysfunction of retinal pigment cells) and so on. More significantly, the loss or dysfunction of cells in the heart (or the vessels that supply the heart with blood) results in heart disease, the most frequent cause of death in California. In 2001 (the most recent year data is available) heart disease caused 68,234 deaths (29% of all the deaths in the state). Stroke is also a vascular disease and the third leading cause of death in California. In 2001, stroke caused 18,088 deaths (8% of all of the deaths in the state). Regenerative medicine represents the effort of cell biologists to invent a new approach to the problem of degenerative disease. 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. It is estimated that are over 200 cell-types in the adult human and hES cells are capable of making all of these. However, to turn this new technology into actual therapies that can alleviate human suffering, researchers need new tools to generate large numbers of purified cell types. This proposal describes a project to identify molecules that could be used to generate large numbers of important cell types from hES cells. The results from the successful completion of this proposed research are anticipated to be useful in numerous therapeutic applications of regenerative medicine.

Analyzing myc function in human embryonic stem cells

Funding Type: 
SEED Grant
Grant Number: 
RS1-00239-A
ICOC Funds Committed: 
$0
Disease Focus: 
Heart Disease
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
A critical open question in regenerative medicine is how to create successful stem cell therapies that yield regenerative growth healing the patient but without giving them cancers which are thought to be the most likely side effect of these types of therapies. One step toward achieving this goal of having human embryonic stem cells (hESC) that are as effective and safe as possible is to identify (1) the stem cell factors that promote the properties of stem cells to regrow organs and (2) the factors that promote cancer formation. With this information we can "customize" hESC to be more functional but not cause cancer. Unfortunately because cancer is a highly related process to regenerative organ growth, the prediction is that the same factors that would tend to enhance the ability of stem cells to mediate regenerative growth are also likely to promote cancer. One example of such factors is the myc family of proto-oncogenes. The main objective of this proposal is to test the hypothesis that the concentration of Myc in hESC determines their regenerative and cancer capacities. We predict that we can identify an optimum amount of Myc that will yield hESC that have enhanced regenerative medicine properties without increased risk of cancer. To this end, we will conduct studies where we selectively raise or lower the amount of Myc in hESC and follow the properties of the "low Myc" hESC, "medium Myc" hESC, and "high Myc" hESC using in vitro assays as well as in vivo assays in mice for regenerative growth in injury models and for tumorigenesis. Our broader goal is to test the novel and risky hypothesis, that we can harness an oncogene to work in a beneficial manner in hESC to promote better regenerative medicine.
Statement of Benefit to California: 
There is great promise in the potential use of human embryonic stem cells (hESC) for regenerative medicine therapies to treat a number of serious medical disorders such as liver disease, blood disorders, neurological disorders, diabetes, heart disease and other conditions. An important place to begin building a foundation for such therapies is to increase our understanding of how hESC function, specifically what makes them more likely to mediate regenerative organ growth and what makes them more likely to cause the unacceptable side effect of cancer. The proposed research, investigating the master regulators of hESC normal and cancerous function, will be of great benefit to the State of California. These studies will promote our ability to use hESC in a safe and effective manner and may allow us to customize hESC lines with an optimum amount of Myc that promotes their beneficial activity while eliminating the risk of cancer.

Targeting nanotherapeutics against acute leukemia stem cells

Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01461
ICOC Funds Committed: 
$0
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
Public Abstract: 
Various cells and organs in the human body originate from a small group of primitive cells called stem cells. Recently, it was found that human cancer cells also arise from a group of special stem cells, named cancer stem cells (CSCs). At present, if cancer has spread throughout the body (metastasized), it is rarely curable, and survival rates in these patients are low. One major reason for therapeutic failure is that CSCs are relatively resistant to current cancer treatments. Although most cancer cells are killed by treatment, resistant CSCs will survive to regenerate additional cancer cells and cause a recurrence of the cancer. As opposed to normal stem cells, CSCs have their own unique molecules on their cell surface. Recently, we have identified several small molecules that can recognize and bind to the unique molecules on CSC. We have also developed a nanotechnology platform to manufacture tiny particles named nanomicelles. These nanomicelles have a size of about 1-2/100th of one micron (one millionth of a meter), and can be loaded with chemotherapy drugs that can kill CSCs. In this project, we will coat the drug-loaded nanomicelles with small molecules that specifically bind and kill CSCs. In patient’s body, these drug-loaded nanomicelles will work like “smart bombs” in a patient’s body. They can identify and bind to CSCs. Therefore, a high concentration of chemotherapy drugs can be delivered to and kill CSCs. Furthermore, chemotherapy drug can be released from nanomicelles to patient’s blood and kill cancer cells throughout the body. With these nanomicelles, both cancer cells and cancer stem cells are targeted, and cancer can possibly be eradicated at its very root. In this project we will focus on one type of cancer called acute myeloid leukemia (AML). It is the most common acute leukemia in adults in the US and a very serious disease. The vast majority of patients with this disease will die either from the disease or from treatment complications. We chose to treat this disease because leukemia cells and leukemia stem cells are located inside the bone marrow or blood vessels that can be easily targeted with our “smart bombs”. We will determine the effectiveness and toxicity of the nanomicelles. After we finish all these experiments, we will discuss with the US Food and Drug Administration (FDA) the requirements for manufacturing the “smart bombs” for human use. In the project’s last year (about 4 years from now), we expect to manufacture sufficient amount of nanomicelles that will meet the quality requirements for clinical trials in human patients with acute myeloid leukemia. We will also write a clinical trial protocol to seek FDA approval for clinical trials in human.
Statement of Benefit to California: 
If this project is successful, it will set up an example of targeting cancer through eradicating cancer stem cells, the cells from which other cancer cells originate. Cancer is the second most common cause of death in California. If cancer can be more effectively treated, the life expectancy can be extended and the quality of life for many cancer patients can be improved. One major aspect of this project is to develop a novel drug delivery system. The drug developed in this project can be used for the treatment of many cancer types. We have shown that chemotherapy drugs delivered in our system are more effective and associated with fewer side effects. Therefore, this project may help improve the treatment outcomes and decrease treatment complications generally associated with cancer therapy. This project may have huge financial benefits to California. Several investigators of this research team have experience in commercializing their discoveries. Several discoveries related to this project have already been filed for patent protection. If this project is successful, some of these patents can be commercialized and bring revenues to California. Acute leukemia is the sixth most common cause of cancer death in males and females in California. The outcome for acute leukemia is poor. Overall, over 70% of patients will die from this disease or treatment-related complications. Patients with acute leukemia usually require intense inpatient chemotherapy that is costly. Many patients die from the complications of treatment. This project aims to develop therapeutic agents that specifically target leukemia stem cells and therefore eradicate leukemia at its root. Furthermore, the agents developed in this project may decrease the side effects of treatment and decrease treatment death. If this project is successful, it will decrease the need for stem cell transplantation, another treatment modality that is associated with even higher treatment-related mortality and cost. Furthermore, many patients cannot undergo stem cell transplantation because it is often difficult to find matched donors for stem cells. This is especially true in California because of the genetically diversified population. If this grant is funded, it will help translate our laboratory research into life-saving clinical applications. There is a huge gap between basic research and clinical applications. This gap is in part traced back to the fact that it is difficult to find researchers who know and can integrate clinical needs with basic research. Many members in this research team have a long track record of bringing bench research into the clinic. If this project is funded, it will not only make this important research possible, but this will also give several of the physician-scientists protected time for translating basic research into clinical applications.
Progress Report: 
  • Disease Team Award DR1-01461, Autologous cardiac-derived cells for advanced ischemic cardiomyopathy, is targeted at developing novel therapies for the treatment of heart failure, a condition which afflicts 7 million Americans. Heart failure, when symptomatic, has a mortality exceeding that of many malignant tumors; new therapies are desperately needed. In the first year of CIRM support, we have developed and validated a development candidate, cardiospheres, which are three-dimensional (3D) functional microtissues engineered in culture and suitable for implantation in the hearts of patients via minimally-invasive catheter-based methods. Cardiospheres, derived from heart biopsies using methods developed by the Principal Investigator, have now been successfuly delivered via magnetically-navigated injection catheters into healthy heart tissue surrounding zones of myocardial damage in preclinical models. The 3D microtissues engraft efficiently in preclinical models of heart failure, as expected from prior work indicating their complex multi-layer nature combining cardiac progenitors, supporting cells and derivatives into the cardiomyocyte and endothelial lineages. We have also developed standard operating procedures for cardiosphere manufacturing, and are in the process of developing release criteria for the 3D microtissue development candidate. Next steps include efficacy studies, with a view to an approved IND by mid-2012.
  • Disease Team Award DR1-01461, autologous cardiac-derived cells for advanced ischemic cardiomyopathy, is targeted at developing novel therapies for the treatment of heart failure, a condition which afflicts 7 million Americans. Heart failure, when symptomatic, has a mortality exceeding that of many malignant tumors; new therapies are desperately needed. In the second year of CIRM support, pivotal pre-clinical studies have been completed. We have found that dose-optimized injection of CSps preserves systolic function, attenuates remodeling, decreases scar size and increases viable myocardium in a porcine model of ischemic cardiomyopathy. The 3D microtissues engraft efficiently in preclinical models of heart failure, as expected from prior work indicating their complex multi-layer nature combining cardiac progenitors, supporting cells and derivatives into the cardiomyocyte and endothelial lineages. Analysis of the MRI data continues. We have developed standard operating procedures for cardiosphere manufacturing and release criteria, product and freezing/thawing stability testing have been completed for the 3D microtissue development candidate. We have identified two candidate potency assays for future development. The disease team will evaluate the results of the safety study (immunology, histology, and markers of ischemic injury) and complete the pivotal pig study in Q1 2012. With data in hand, full efforts will be placed on preparation of the IND for Q2 2012 submission.

Efficient T cell development from human pluripotent stem cells by LRF/Pokemon inactivation

Funding Type: 
Basic Biology I
Grant Number: 
RB1-01354
ICOC Funds Committed: 
$0
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 
T cells (or T lymphocytes) are necessary for normal immune surveillance systems, and their dysfunction leads to development of fatal diseases, such as Acquired Immune Deficiency Syndrome (AIDS), congenital T cell deficiency and cancer. These diseases are life threatening, because T cells, key effectors eradicating pathogens within the body, are severely reduced and medications (e.g. anti-viral treatment) cannot fully compensate for such fundamental defects. Thus, in these circumstances, providing T cells to the patient, so-called “T cell replacement therapy”, could be the sole therapeutic option to cure the disease. However, such therapy has not been successfully established because of the following reasons: 1) T cells are difficult to expand in culture; 2) even if the patient’s T cells can be expanded in culture, they may not work normally when they are returned to the patient (e.g. T cells will be again infected with HIV virus) and 3) T cells from others (donor) could recognize the patient (recipient) as "foreign" and mount an immunologic attack. Human pluripotent stem cells, such as human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs), have tremendous potential in T cell replacement therapy, as: 1) they are virtually unlimited; 2) patient-specific hiPSCs can overcome immunological barriers between donors and recipients and 3) hESCs/hiPSCs could be safely manipulated for T cells to be functional. While T cells have been successfully derived from mouse embryonic stem cells (mESCs), hESCs demonstrated little lymphoid potential, preventing the use of hESCs for T cell replacement therapy. Considering clinical implications, there is a critical need to better understand the mechanisms underlying hESCs/hiPSCs differentiation toward T cells. Our goal is to develop a system by which hESCs/hiPSCs efficiently give rise to T cells in culture. The objective of this application is to determine the role of the Leukemia/lymphoma Related Factor (LRF) gene in human T cell differentiation from hESCs/hiPSCs. Guided by our preliminary studies, we hypothesize that LRF inactivation promotes efficient T cell development from hESCs/hiPSCs. We will test this hypothesis employing molecular biological approaches as well as a series of genetically engineered mouse models. We expect that the combination of work proposed will provide further understanding of how hESCs/hiPSCs develop T cells in culture. This contribution is significant because it will lead to the development of new therapeutic strategies for T cell replacement therapy.
Statement of Benefit to California: 
T cells are essential for human immune system and the lack of functional T cells results in development of diseases such as AIDS, sever infectious diseases and cancer. These diseases are one of the major health issues in California. It has been estimated that nearly 130,000 people in California live with human immunodeficiency virus (HIV) infection, among which 70,000 are diagnosed as AIDS (HIV Prevalence Estimates of California, CDC, 2008). For these patients, providing healthy and functional T cells, so-called T cell replacement therapy, could be a new therapeutic strategy, as current therapies (e.g. anti-viral drag for AIDS, chemotherapy for cancer) cannot cure the disease, and cost of the treatment is high. Human pluripotent stem cells (hPSCs) are a very promising source for such T cells, as they are virtually unlimited and relatively easy to be manipulated in culture (e.g. gene therapy for AIDS and cancer). However, it is not fully understood how hPSCs differentiate to T cells, preventing their use in the clinic. Our goal is to develop a new way of creating T cells from hPSCs in culture by elucidating the molecular mechanisms of T cell development from hPSCs. If successful, it will provide the people of California with tremendous benefits, potentially leading to new therapeutic strategies for life-threatening diseases such as cancer and AIDS. It may also lead to the significant reduction of therapeutic costs, thus benefiting the State economy.
Progress Report: 
  • In this application, we propose to study the growth and differentiation properties of an authentic endogenous human cardiac progenitor cells (CPCs) that can differentiate into cardiac muscle cells, smooth muscle cells and endothelial cells. We have isolated these multipotent CPCs from human ventricles and human induced pluripotent cells and compared therie differentiation potential. Additionally, we have characterized a cardiac niche in the developing heart, demonstrated that both the extracellulat matrix molecules and the three dimensional environment is important for CPC renewal. We believe these experiments will significantly advance out understanding of the biology of CPCs and facilitate their application as a regenerative therapy.
  • In this application, we propose to study the growth and differentiation properties of an authentic endogenous human cardiac progenitor cells (CPCs) that can differentiate into cardiac muscle cells, smooth muscle cells and endothelial cells. We have isolated these multipotent CPCs from human ventricles and human induced pluripotent cells and compared therie differentiation potential. Additionally, we have characterized a cardiac niche in the developing heart, demonstrated that both the extracellulat matrix molecules and the three dimensional environment is important for CPC
  • renewal. We believe these experiments will significantly advance out understanding of the biology of CPCs and facilitate their application as a regenerative therapy.

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