Liver Disease

Coding Dimension ID: 
301
Coding Dimension path name: 
Metabolic Disorders / Liver Disease
Grant Type: 
Early Translational III
Grant Number: 
TR3-05488
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 750 375
Disease Focus: 
Liver Disease
Metabolic Disorders
Pediatrics
Human Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 

Approximately 1 in 1,500 children has a congenital metabolic disorder. These inborn errors of metabolism are caused by deficiencies of different enzymes and result in accumulation of various substances inside cells. These substances affect the function of vital organs, and in many cases are lethal. Transplantation of cells that possess the particular deficient enzyme carries the potential to cure these diseases. Currently, a shortage of human liver cells for transplantation prohibits clinical use of this therapy. The human placenta contains cells that may acquire hepatic function. Following delivery of a baby, these cells can be collected from the placenta which is in most cases is treated as medical waste and discarded. The therapeutic potential of this cell type has been shown in animal models. We propose to first develop a method to separate these cells from non liver like cells, and secondly use these cells to treat multiple mouse models of human inborn errors of metabolism. We will also establish a clinically applicable small-scale preparatory Bio-banking system to provide immunotype-matched cells to patients affected by these diseases. These immunotype-matched cells can replace the missing enzyme function in patients who suffer from congenital liver metabolic disorders, and potentially will be cure the condition. Although this proposal focuses on the congenital liver metabolic disorders, success may lead to the use of these cells in other liver diseases.

Statement of Benefit to California: 

We propose to develop a technology to isolate and derive functional hepatic cells from discarded human placentae. The therapeutic cells will be utilized to treat congenital metabolic disorders. Current therapy for congenital metabolic disorders requires life-long treatment. It is easy to imagine how the economical burden afflicts the patients' families and society. If successful, immuotype matched hAEC-derived cell replacement therapy may completely cure some of the congenital metabolic disorders. The benefit of this new regenerative medicine will be tremendous not only for the patients' quality of life but also for our society. Although this proposal focuses on the congenital liver metabolic disorders, the target disease can potentially be extended to other liver diseases. This cell therapy would be the first cell therapy for liver disease and could benefit thousands of patients in California who suffer various liver diseases.
Furthermore, once this therapeutic potential is demonstrated, a placenta collection system, placental stem cell banking system, and a stem cell-derived hepatic cell distribution system might be a novel industry or industries that could provide job opportunities to the citizens of California.

Grant Type: 
Early Translational III
Grant Number: 
TR3-05542
Investigator: 
ICOC Funds Committed: 
$1 544 170
Disease Focus: 
Liver Disease
Metabolic Disorders
Collaborative Funder: 
China
Human Stem Cell Use: 
Directly Reprogrammed Cell
oldStatus: 
Active
Public Abstract: 

Although the liver can regenerate itself, chronic or overwhelming damage can cause life-threatening liver failure. Currently, the only therapy for liver failure is liver transplantation. Because the supply of cadaveric livers or liver tissue from living donors far exceeds the demand, physicians and researchers seek to develop new therapies to save the lives of patients with liver failure. One promising strategy is transplantation of hepatocytes, the cells of the liver that provide most of its functions and that are defective in liver failure. To make hepatocyte transplantation available to all patients who could benefit, a cell source other than scarce donor livers has to be established. In contrast to hepatocytes, skin cells can be readily obtained and expanded in culture. Therefore, the recent discovery that skin cells can be converted into hepatocytes by transfer of a few genes suggests a promising new source of hepatocytes. To develop transplantation of such cells as a therapy for liver failure, we aim to identify which readily available human cell type—skin, blood or fat cells—can be most efficiently converted into hepatocytes using methods of temporary gene transfer. Importantly, the therapeutic efficacy and safety of these induced hepatocytes will be rigorously tested in animal models of human liver failure. If successful, our project will establish the feasibility of therapy of liver failure with cells derived from a patient’s own readily available non-liver cells.

Statement of Benefit to California: 

Like in most states in the US, the number of Californians in need of a liver transplant significantly exceeds the number of available donor organs. Most of these patients have liver cirrhosis due to hepatitis C infection, alcoholic liver disease or cholestatic diseases. Other indications for liver transplantation include acute liver failure, hepatitis B virus infection, metabolic liver diseases and cancer. While the incidence of these liver diseases has been relatively stable, non-alcoholic steatohepatitis (NASH), which was first described only 10 years ago, is rapidly emerging and predicted to become the leading indication for liver transplantation in the future. Because Hispanics have an increased risk of developing NASH, California, the state with the largest Hispanic population in the US, will be particularly impacted by this epidemic. Thus, developing an abundant source of cells for liver cell therapy, as proposed in this project, will not only benefit the Californians currently awaiting liver transplantation, but may also help the state’s medical system to respond to this future challenge.

Grant Type: 
Tools and Technologies II
Grant Number: 
RT2-02060
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 869 487
Disease Focus: 
Blood Disorders
Heart Disease
Liver Disease
Metabolic Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Active
Public Abstract: 

Purity is as important for cell-based therapies as it is for treatments based on small-molecule drugs or biologics. Pluripotent stem cells possess two properties: they are capable of self regeneration and they can differentiate to all different tissue types (i.e. muscle, brain, heart, etc.). Despite the promise of pluripotent stem cells as a tool for regenerative medicine, these cells cannot be directly transplanted into patients. In their undifferentiated state they harbor the potential to develop into tumors. Thus, tissue-specific stem cells as they exist in the body or as derived from pluripotent cells are the true targets of stem cell-based therapeutic research, and the cell types most likely to be used clinically. Existing protocols for the generation of these target cells involve large scale differentiation cultures of pluripotent cells that often produce a mixture of different cell types, only a small fraction of which may possess therapeutic potential. Furthermore, there remains the real danger that a small number of these cells remains undifferentiated and retains tumor-forming potential. The ideal pluripotent stem cell-based therapeutic would be a pure population of tissue specific stem cells, devoid of impurities such as undifferentiated or aberrantly-differentiated cells.
We propose to develop antibody-based tools and protocols to purify therapeutic stem cells from heterogeneous cultures. We offer two general strategies to achieve this goal. The first is to develop antibodies and protocols to identify undifferentiated tumor-forming cells and remove them from cultures. The second strategy is to develop antibodies that can identify and isolate heart stem cells, and blood-forming stem cells capable of engraftment from cultures of pluripotent stem cells. The biological underpinning of our approach is that each cell type can be identified by a signature surface marker expression profile.
Antibodies that are specific to cell surface markers can be used to identify and isolate stem cells using flow cytometry. We can detect and isolate rare tissue stem cells by using combinations of antibodies that correspond to the surface marker signature for the given tissue stem cell. We can then functionally characterize the potential of these cells for use in regenerative medicine.
Our proposal aims to speed the clinical application of therapies derived from pluripotent cell products by reducing the risk of transplanting the wrong cell type - whether it is a tumor-causing residual pluripotent cell or a cell that is not native to the site of transplant - into patients. Antibodies, which exhibit exquisitely high sensitivity and specificity to target cellular populations, are the cornerstone of our proposal. The antibodies (and other technologies and reagents) identified and generated as a result of our experiments will greatly increase the safety of pluripotent stem cell-derived cellular therapies.

Statement of Benefit to California: 

Starting with human embryonic stem cells (hESC), which are capable of generating all cell types in the body, we aim to identify and isolate two tissue-specific stem cells – those that can make the heart and the blood – and remove cells that could cause tumors. Heart disease remains the leading cause of mortality and morbidity in the West. In California, 70,000 people die annually from cardiovascular diseases, and the cost exceeded $48 billion in 2006. 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. Similarly, diseases of the blood-forming system, e.g. leukemias, remain a major health problem in our state.
hESC and induced pluripotent stem cells (collectively, pluripotent stem cells, or PSC) could provide an attractive therapeutic option to treat patients with damaged or defective organs. PCS can differentiate into, and may represent a major source of regenerating, cells for these organs. However, the major issues that delay the clinical translation of PSC derivatives include lack of purification technologies for heart- or blood-specific stem cells from PSC cultures and persistence of pluripotent cells that develop into teratomas. We propose to develop reagents that can prospectively identify and isolate heart and blood stem cells, and to test their functional benefit upon engraftment in mice. We will develop reagents to identify and remove residual PSC, which give rise to teratomas. These reagents will enable us to purify patient-specific stem cells, which lack cancer-initiating potential, to replenish defective or damaged tissue.
The reagents generated in these studies can be patented forming an intellectual property portfolio shared by the state and the institutions where the research is carried out. The funds generated from the licensing of these technologies will provide revenue for the state, will help increase hiring of faculty and staff (many of whom will bring in other, out-of-state funds to support their research) and could be used to ameliorate the costs of clinical trials – the final step in translation of basic science research to clinical use. Only California businesses are likely to be able to license these reagents and to develop them into diagnostic and therapeutic entities; such businesses are at the heart of the CIRM strategy to enhance the California economy. Most importantly, this research will set the platform for future stem cell-based therapies. Because tissue stem cells are capable of lifelong self-renewal, stem cell therapies have the potential to be a single, curative treatment. Such therapies will address chronic diseases with no cure that cause considerable disability, leading to substantial medical expense. 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.

Grant Type: 
Early Translational II
Grant Number: 
TR2-01857
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$5 199 767
Disease Focus: 
Liver Disease
Metabolic Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

Because there is still considerable morbidity and mortality associated with the process of whole liver transplantation, and because more than a thousand people die each year while on the liver transplantation list, and tens of thousands more never get on the list because of the lack of available livers, it is evident that improved and safer liver transplantation would be valuable, as would approaches that provide for an increased number of transplantations in a timely manner. A technology that might address these issues is the development of a human liver cell line that can be employed in liver cell transplantation or in a bioartificial liver. Developing such a cell line from human embryonic stem cells (hESC) would provide a valuable tool for pharmacology studies, as well as for use in cell-based therapeutics. The objective of this proposal is to focus a team effort to determine which differentiated hESC will be the most effective liver-like cells in cell culture and in animal studies, and to then use the best cells in clinical trials of cell transplantation in patients with advanced liver disease.

In the proposed studies, the team will differentiate hESC so that they act like liver cells in culture. Once it has been established that the cells are acting like liver cells by producing normal human liver proteins, and that they do not result in tumors, the cells will be assessed in clinically-relevant models using techniques that can then be adapted to future human clinical trials. One of the ways cells can be evaluated is to label the cells which will provide a means to monitor them with various imaging systems. The intent in these studies is to determine which will be the most effective cells to use in human clinical trials. Once this is determined, the best cells can then be employed in human patients.

If the studies are successfully undertaken, we will have established a clinically useful and viable liver cell line that could be used to repopulate an injured liver in a safer and less expensive manner than with whole liver transplantation. Moreover, all people who have liver failure or an inherited liver disease could be treated, because there would be an unlimited supply of liver cells.

Statement of Benefit to California: 

In California, as in all parts of the US, there are not enough livers available for transplantation for all the people who need them. The result is that many more people die of liver failure than is necessary. One way to improve this situation is the transplantation of liver cells rather than whole organ transplantation. We are attempting to develop liver cell lines from stem cells that will act like normal liver cells. If the cells that we develop function well and do not act like cancer cells in culture, the cells will be assessed in clinically-relevant models using techniques that can then be adapted to future human clinical trials. In our studies, we will compare human embryonic stem cells with other stem cells to determine which will be the most effective cells to transplant into people. In the future, we will employ the best cells in clinical trials in humans. If the studies are successfully undertaken, we will have established a clinically useful and viable liver cell line that could be used to repopulate an injured liver in a safer and less expensive manner than with whole liver transplantation. Moreover, all people who have liver failure or an inherited liver disease could be treated, because there would be an unlimited supply of liver cells.

Grant Type: 
Tools and Technologies I
Grant Number: 
RT1-01012
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$971 558
Disease Focus: 
Liver Disease
Metabolic Disorders
Toxicity
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Drug-induced liver toxicity, including that from FDA-approved drugs, is the leading cause of liver failure in the US. One of the biggest road blocks to testing drug-induced liver toxicity prior to clinical studies or release of the drug into the market is the absence of a good model of human drug metabolism in the liver. Development of a clinically predictive drug screening system would allow earlier detection of drug-induced liver toxicity, thus decreasing drug costs, decreasing the scale of pre-clinical animal testing, and increasing drug safety. Unfortunately, use of primary human liver cells for drug screening is hampered by their limited availability and poor viability in culture. Human embryonic stem (hES) cells, however, could provide a renewable, scalable, relevant source of liver cells since they can be induced to turn into these types of cells. Unfortunately, though, current hES protocols yield primarily immature liver cells, even though mature adult-like liver cells would be needed for drug screening. Here we propose development of a new hES cell line tool that attaches a fluorescent molecule to a protein found in mature liver cells. This would be a very powerful tool for two key avenues of study and development. First, it will facilitate testing of new methods to enhance the maturation of hES-derived liver cells, ultimately leading to better protocols for transplantation and regenerative medicine purposes. Second, it will also be instrumental in screening for drug-induced liver toxicity effects. While [REDACTED] interests lie more with the usage of this tool for drug screening purposes, we plan to openly share this tool with the scientific community under standard licensing agreements so that rapid progress can be made in both these areas.

Statement of Benefit to California: 

This proposal has been submitted by a California company whose mission is to develop and commercialize ES cell-based assays to aid in drug discovery and development. Using stem cells to model how the liver metabolizes drugs would lead to earlier detection of drug-induced liver toxicity, keeping many of the more dangerous clinical drugs from ever reaching the market. This would increase drug safety, decrease drug costs, and decrease the scale of pre-clinical animal testing that is currently used in drug development benefiting all Californians.

The work outlined in this proposal will also bring significant revenue into California, in various different forms. Whenever possible, we will continue to order supplies and/or use services through our standing relationships with California vendors, such as E&K Scientific (Santa Clara, CA), Invitrogen (Carlsbad, CA), and Stanford University Core Research facilities in order to support California businesses and universities. Partnering and licensing of the technology developed in this proposal, as well as commercialization of new and safer drugs, would bring revenue and additional jobs into California. In addition, patents arising from these technologies are also potentially significant for California, due to the licensing revenue fees that would go back to the state.

The ES cell line tool generated as a result of this proposal, along with the reagents used to make it, will be shared openly with the scientific community under transfer and/or licensing agreements that are standard to both academic and industrial scientific entities. This will facilitate rapid progress toward two key avenues of research and development: 1) screening drugs for potential toxic effects on the liver and 2) for better understanding liver development, ultimately leading to better protocols for transplanting ES-derived liver cells into patients with liver disease or drug-induced liver toxicity. This would also result in more jobs in California to carry out this work and would form the basis of additional academic and corporate collaborations that would increase California's leadership role in stem cell applications.

Grant Type: 
New Faculty II
Grant Number: 
RN2-00950
Investigator: 
ICOC Funds Committed: 
$3 032 510
Disease Focus: 
Liver Disease
Metabolic Disorders
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

The liver is a promising target for cell therapy since it supports and functionally integrates transplanted cells. Human liver contains more than 50 billion cells and more than 10% replacement will be required for most liver diseases. Hence, embryonic stem cells (ESC), which have unlimited growth capacities, represent one of the few cell types with potential for liver cell therapy. However, to be functionally effective and safe, ESC have to be differentiated into hepatocytes, the cells of the liver that provide its typical functions, before transplantation. Unfortunately, current ESC differentiation protocols generate cells that are not fully differentiated or functional. To achieve levels of differentiation that would be therapeutic we propose to identify the mechanisms that establish hepatocyte function in progenitor cells in the adult liver. Adult liver progenitors are typically absent from the normal liver but become apparent in liver disease when hepatocytes are damaged. Remarkably, adult liver progenitors can differentiate into fully functional hepatocytes within a few days. We hope to identify the genes that enable this rapid maturation process in order to apply it to immature cells derived from ESC. If maturation can be induced and these hepatocyte-like cells function to correct a mouse model of a human liver disease we will have provided proof-of-principle for the potential of ESC for liver cell therapy.

Statement of Benefit to California: 

Liver transplantation is the only curative option for patients with severe liver diseases. As donor livers are rare, many Californians are currently waiting to receive a transplant. In fact, many patients on the waiting list die before a donor organ becomes available. If successful, the proposed project would help to alleviate the need for donor organs by establishing embryonic stem cells as a source of hepatocytes for transplantation. As hepatocyte transplantation would be less invasive and expensive than orthotopic liver transplantation, funds might become available that could be used to benefit the citizens of California in other areas.

Grant Type: 
Comprehensive Grant
Grant Number: 
RC1-00359
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$2 504 614
Disease Focus: 
Liver Disease
Metabolic Disorders
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Because there is still considerable morbidity and mortality associated with the process of transplantation, and because more than a thousand people die each year while on the liver transplantation list, it is evident that improved and safer liver transplantation would be valuable, as would approaches that provide for an increased number of transplantations in a timely manner. A technology that might address these issues is the development of a human liver cell line that can be employed in liver cell transplantation or in a bioartificial assist device. Developing such a cell line from human embryonic stem cells (hESC) or from other human stem cell sources would provide a valuable tool for pharmacology studies, as well as for use in cell-based therapeutics.

In the proposed studies, we will differentiate human embryonic stem cells or fetal liver cells or bone-marrow derived cells so that they act like liver cells in culture. Once it has been established that the cells are acting like liver cells by producing normal human liver proteins, and that they do not act like cancer cells, the cells will be injected into the livers of immunoincompetent mice that do not rejects human cells. Then we will evaluate whether the cells grow and thrive in the mouse livers, whether they still produce high levels of human liver-specific proteins, whether they produce tumors in the mouse livers, and whether they can replace damaged mouse liver cells with human cells. One of the ways this will be done is to label the cells with a marker gene and to image the marker gene in the livers of the mice with special x-ray machines that can distinguish a few hundred human cells in the mouse liver. Finally, we will infuse the human liver stem cells into the liver of monkeys to determine if they will grow in the monkey livers, because the monkeys are more similar to man. Such studies should be done in nonhuman primates before clinical studies are undertaken to employ these cells to replace abnormal liver cells in man. Our intent is these studies is to compare and contrast three types of stem cells to determine which will be the most effective cells to use in human studies.

If the studies are successfully undertaken, we will establish a clinically useful and safe liver cell line that could be used to repopulate an injured liver in a safer and less expensive manner than with liver transplantation; moreover, all people who had liver failure or an inherited liver disease could be treated, because there would be an unlimited supply of liver cells.

Statement of Benefit to California: 

In California, as in all parts of the US, there are not enough livers available for transplantation for all the people who need them. The result is that many more people die of liver failure than is necessary. One way to improve this situation is the transplantation of liver cells rather than whole organ transplantation. We are attempting to develop liver cell lines from stem cells that will act like normal liver cells. If the cells that we develop function well and do not act like cancer cells in culture, we will then transplant them into special mouse models of liver disease and see if the human cells can rescue the mouse from its liver disease. As a final test, we will see if the cells function in primate livers. In our studies, we will compare human embryonic stem cells with adult stem cells to determine which will be the most effective cells to transplant into people. If the studies are successfully undertaken, it means that we will have a stem cell line that can then be employed in human studies to determine their safety and effectiveness.

Pages