Liver Disease

Coding Dimension ID: 
301
Coding Dimension path name: 
Metabolic Disorders / Liver Disease

iPSCs as a screening tool to predict risk of nonalcoholic fatty liver disease

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-12358
Investigator: 
ICOC Funds Committed: 
$813 000
Disease Focus: 
Liver Disease
Metabolic Disorders
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

Research Objective

The objective of this proposal is to established undifferentiated iPSCs as a diagnostic tool for the prediction of nonalcoholic fatty liver disease onset and severity.

Impact

Despite the widespread estimated prevalence of NAFLD, there are currently no tools available to predict likelihood of NAFLD susceptibility beyond standard clinical and demographic information.

Major Proposed Activities

  • Create an iPSC-based NAFLD risk score (iPSC-RS) by defining threshold values for oleate-induced intracellular lipid accumulation that distinguish iPSCs from NAFLD patients versus healthy controls.
  • Validate the iPSC-RS in an independent set of iPSCs from 25 NAFLD cases and 25 healthy controls, and evaluate the it's reproducibility across biological replicates and independent laboratories.
  • Compare the validated iPSC-RS to other NAFLD risk predictors based on genomic information alone.
Statement of Benefit to California: 

Nonalcoholic fatty liver disease (NAFLD) is a widely undiagnosed condition, and is estimated to impact up to 30% of adults. NAFLD is most prevalent in Hispanics, with the absolute highest levels found in individuals of Mexican ancestry, and thus is relevant to California's LatinX population. As NAFLD is anticipated to become the leading cause of liver transplant, identifying Californians most at risk could address significant gaps in screening and prevention for this serious disease.

Universal Pluripotent Liver Failure Therapy (UPLiFT)

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10979
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 297 512
Disease Focus: 
Liver Disease
Metabolic Disorders
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

Research Objective

Universal Pluripotent Liver Failure Therapy (UPLiFT) is composed of 2 lines- UPLiFT0 ( from LiPSC-GR1.1) and UPLiFT1 which will be derived from gene edited universal human pluripotent stem cells.

Impact

In some liver-based metabolic diseases, replacement of 5-10% of the liver mass may salvage the patient. Transplantation of hepatic progenitors from universal donor cells might avoid immunosuppression.

Major Proposed Activities

  • Developing and testing a cGMP-compliant manufacturing protocol for differentiating LiPSC-GR1.1 and the gene edited universal version of these cells into hepatic progenitors.
  • Production of sufficient cells of UPLiFT0 (LiPSC-GR1.1) and UPLiFT1 (Universal donor) sufficient to perform Milestones 3-5 including mouse studies
  • UPLiFT Function and Fate: In our established in vivo model of hepatic stem/progenitor cell transplantation, assess the maturation, proliferation, and function of transplanted hepatic progenitor cells
  • Select dose, determine regiment and route of administration. In tested model of hepatic failure establish effective dose and regimen
  • Pilot preclinical safety/toxicology/long term outcomes at the optimal dose and route, assess off-target effects.
  • Preparation of Pre-Pre IND Package and Scheduling/Conduct of Pre-Pre IND meeting
Statement of Benefit to California: 

California has the 12th highest death rate of liver disease in the US. The worldwide burden of liver disease is around 30 million patients, affecting one in ten in the US. Liver-based metabolic diseases are a rational starting point to apply cellular therapy to liver disorders. In some congenital metabolic disorders, replacement of 5-10% of the native liver mass may salvage the patient from the buildup of toxic metabolites. Our proposed cell therapy might expand treatment options.

Towards hepatocyte cell replacement therapy: developing a renewable source of human hepatocytes from pluripotent stem cells

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10679
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$2 201 136
Disease Focus: 
Liver Disease
Metabolic Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Research Objective

To develop a consistent and abundant source of transplantable human hepatocytes for transplantation.

Impact

Developing an abundant and consistent source of human hepatocytes that can be used to treat patients with liver failure.

Major Proposed Activities

  • To determine the degree by which human pluripotent stem cell (hPSC)-derived hepatocytes engraft and restore liver function in mouse models of liver injury
  • To assess long-term safety of transplanted hepatocytes in vivo
  • To track long-term localization and cell-growth of transplanted hPSC-derived hepatocytes after transplantation into injured mouse livers
  • To profile cell-type specific surface markers expressed on hPSCs and hPSC-derived hepatocytes
Statement of Benefit to California: 

Liver failure is one of the 12 leading causes of adult death in the U.S. The only long-term treatment for liver failure is to transplant a new liver, but there is a grim shortage in available livers, with many patients dying while awaiting a suitable liver. Our research aims to generate large numbers of human liver cells derived from stem cells that could one day be used to treat patients with liver disease and end-stage liver failure.

Preclinical development of AAV vector-mediated in vivo hepatic reprogramming of myofibroblasts as a therapy for liver fibrosis

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10088
Investigator: 
ICOC Funds Committed: 
$1 638 389
Disease Focus: 
Liver Disease
Metabolic Disorders
Human Stem Cell Use: 
Directly Reprogrammed Cell
Public Abstract: 

Research Objective

An intravenously injectable virus that converts the scar cells responsible for liver cirrhosis into the cells that provide most of the liver’s function, thereby preventing or reversing liver failure.

Impact

The proposed research will develop a new therapy for liver cirrhosis, which can be cured by liver transplantation, but there are not enough donor organs for all patients in need.

Major Proposed Activities

  • Construction of a single AAV vector expressing the human transcription factors FOXA3, HNF1A and HNF4A effective in hepatic reprogramming of human myofibroblasts.
  • Identification of chimeric AAV capsids that transduce human myofibroblasts in vivo with high efficiency and specificity.
  • Identification of human myofibroblast-targeted chimeric AAV capsids that are not neutralized by human antibodies against naturally occurring AAV capsids.
  • Demonstration of therapeutic efficacy and principal safety of in vivo hepatic reprogramming of human myofibroblasts.
Statement of Benefit to California: 

California has one of the longest wait times for a donor liver in the US. Therefore, many Californians with liver cirrhosis have to be hospitalized or die while waiting for a transplant. By developing a broadly applicable new therapy for liver cirrhosis, the proposed research will improve the outcomes of patients with liver cirrhosis and reduce the financial burden on California’s medical system.

Preclinical development of human hepatocyte progenitor cells for cell therapy

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-09565
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 655 436
Disease Focus: 
Liver Disease
Metabolic Disorders
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Research Objective

Determine if human hepatocyte progenitor cells, which exist in the normal adult liver, can be maintained and expanded in vitro while maintaining in vivo regenerative capacity.

Impact

Cell transplantation therapy can be an effective alternative treatment for severe liver diseases to liver transplantation, which is severely limited by the lack of available donor organs.

Major Proposed Activities

  • Characterize human pericentral hepatocytes and their niche in normal adult human liver
  • Determine if human pericentral hepatocytes function as progenitor cells in a humanized mouse liver model
  • Compare the regenerative capacity of human HPCs with mature hepatocytes
  • Determine the optimum in vitro conditions for maintaining and expanding human HPCs
  • Examine whether endothelial cells promote in vitro expansion of human HPCs
  • Assess the liver repopulating capability of long-term culture expanded HPCs
Statement of Benefit to California: 

Cellular therapy for severe liver disease in the form of hepatocyte transplantation is effective alternative to whole organ transplantation. However, its usage is limited by the severe shortage of healthy primary human hepatocytes. The potential to generate patient-specific sources of hepatocytes from HPCs for cellular therapy would address an immense unmet clinical need.

Generation of bile duct-competent transplantable human liver organoids

Grant Type: 
Inception - Discovery Stage Research Projects
Grant Number: 
DISC1-08792
Investigator: 
ICOC Funds Committed: 
$206 460
Disease Focus: 
Liver Disease
Metabolic Disorders
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

Research Objective

Generation of human stem cell-derived mini livers capable of exporting bile into the gallbladder after transplantation into the liver

Impact

Mini livers capable of normal bile export would have potential for therapy of diseases in which bile export is impaired like Alagille syndrome

Major Proposed Activities

  • Generation of mini livers using human stem cell-derived liver cells of different levels of maturity
  • Identification of human stem cell-derived mini livers that are most effective in exporting bile into the gallbladder after transplantation into the livers of mice modeling Alagille syndrome
  • Assessment and, if necessary, improvement of function, structure and growth of human stem cell-derived mini livers after transplantation into the livers of mice
Statement of Benefit to California: 

Many citizens of the state of California are in need for liver transplantation because of liver diseases associated with impaired bile flow. Because donor livers are sparse, many of these patients die while waiting for liver transplantation. Our research may generate a therapy that stabilizes liver function until a donor liver becomes available or may avoid the need for liver transplantation.

Development of a clinical-grade extracorporeal liver support system using human induced pluripotent stem cell-derived hepatic cells

Grant Type: 
Tools and Technologies III
Grant Number: 
RT3-07670
Investigator: 
Name: 
Institution: 
Type: 
PI
Name: 
Institution: 
Type: 
Partner-PI
ICOC Funds Committed: 
$1 393 290
Disease Focus: 
Liver Disease
Metabolic Disorders
Collaborative Funder: 
Germany
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

Liver failure is the fourth leading cause of adult death in California. Because liver cells can regenerate, some patients with liver failure could be saved without having to undergo organ transplantation if their liver function could be supported temporarily. Here, we propose to develop a device to support these patients called the “extracorporeal liver support system (ELS).”

Numerous pre-clinical studies and clinical trials have demonstrated the therapeutic effectiveness of ELS using human or animal liver cells housed in a device outside of the patient’s body but connected to the patient's circulation. The device removes toxins and prevents irreversible brain damage while the patient regenerates his or her own liver cells. However, the limited availability of human cells and insufficient functionality of animal cells prohibits this therapy from being widely adopted.

For this project, we will develop ELS using human stem cell-derived liver cells (hPSC-Hep) that will overcome two major bottlenecks in the translation of human stem cell therapies: scalability and safety. The unlimited supply and consistent quality of hPSC-Hep will allow us to make ELS scalable. By keeping the hPSC-Hep in a device separate from the patient’s body, we will also be able to allay any safety concerns about these cells forming tumors.

The result will be a widely available, safe and effective treatment that will alleviate the need for liver transplants for certain patients.

Statement of Benefit to California: 

Liver disease is a leading cause of death in California. California’s rate of 10.6 deaths per 100,000 people exceeds the national average of 8.8. To mitigate this problem, we propose developing a clinical device that can temporarily perform liver functions until a patient’s own liver cells recover. The device will use stem cells as a source of unlimited and quality controlled liver cells. Because the device is outside of the patient’s body, these stem cell-derived liver cells will remain separate from the patient’s blood stream, overcoming any risk of tumor formation. If successful, the device will be the leading choice for treatment, and will allow patients to recuperate without undergoing costly liver transplantation, which places an economic burden on patients' families as well as society.
Furthermore, the production of this device could constitute a novel industry that would provide job opportunities to the citizens of California. If successful, our industrial partner plans to launch a new California-based company in the near future.
The benefits of this new regenerative therapy will have a tremendous impact on the state of California and the thousands of patients suffering from liver diseases.

Gene therapy-corrected autologous hepatocyte-like cells from induced pluripotent stem cells for the treatment of pediatric single enzyme disorders

Grant Type: 
Early Translational IV
Grant Number: 
TR4-06831
Investigator: 
ICOC Funds Committed: 
$1 801 629
Disease Focus: 
Genetic Disorder
Liver Disease
Metabolic Disorders
Pediatrics
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

Liver transplantation (LT) has been used to treat a variety of liver diseases. Within hours after birth, neonates can present with disorders of the urea cycle (UCDs), the critical metabolic liver pathway needed to detoxify waste nitrogen from the diet and cellular turnover. The overall incidence of UCDs is estimated to be 1 in 8200 births. An increase in ammonia concentrations is particularly toxic to the central nervous system (CNS), causing brain edema, with multiple episodes affecting survival and often resulting in mental retardation and cerebral palsy. While LT is recommended in neonatal-onset patients with these single-enzyme defects, organ availability is a major limitation and transplantation requires lifelong immunosuppression. In addition, transplant morbidity and mortality are not inconsequential: 1-year survival is about 91.9%, and 5-year survival in children transplanted at less than 5 kg is 74%. Transplantation of genetically corrected embryonic stem cell-derived hepatocytes from the affected patients themselves is a potential way to replace LT for the treatment of metabolic liver disease and will likely not require immunosuppression; importantly, the supply will be limitless, allowing early transplantation before CNS injury. We propose to explore this approach by using a new and robust liver repopulation UCD mouse to advance this therapy: treatment of single-enzyme liver defects with patient-derived and genetically corrected stem cell-induced liver cells.

Statement of Benefit to California: 

Unfortunately there is a substantial wait for people in California who need a liver transplant, resulting in many who develop significant disability or die while waiting. While many are adults with chronic disease, some are children with metabolic disorders including urea cycle disorders (UCDs).

UCDs are caused by mutations resulting in enzyme deficiencies responsible for removing waste nitrogen, which as ammonia can cause irreversible brain damage, coma and/or death. Newborns can become catastrophically ill within 36-48 hours after birth. These and other inborn errors represent a substantial cause of brain damage and death among newborns and infants and because many cases remain undiagnosed, or infants with the disorders die without a definitive diagnosis, the exact incidence is unknown and likely underestimated.

Present treatment is dietary for most which is onerous & incomplete; definitive therapy is liver transplantation which is challenging in infants who have greater rates of complications and morbidity. In this proposal we will develop genetically-corrected hepatocyte-like cells from induced pluripotent stem cells from patients with arginase deficiency, a UCD. These will be tested for the ability to correct the disorder in a unique UCD liver repopulation animal model. The advantage of the proposed methodology over current therapy is that genetically-corrected cells will be limitless and will require no major surgery or immunosuppression and its short- & long-term risks.

Development of a cell and gene based therapy for hemophilia

Grant Type: 
Early Translational IV
Grant Number: 
TR4-06809
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$2 322 440
Disease Focus: 
Blood Disorders
Liver Disease
Metabolic Disorders
Pediatrics
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 

Hemophilia B is a bleeding disorder caused by the lack of FIX in the plasma and affects 1/30,000 males. Patients suffer from recurrent bleeds in soft tissues leading to physical disability in addition to life threatening bleeds. Current treatment (based on FIX infusion) is transient and plagued by increased risk for blood-borne infections (HCV, HIV), high costs and limited availability. This has fueled a search for gene/cell therapy based alternatives. Being the natural site of FIX synthesis, the liver is expected to provide immune-tolerance and easy circulatory access. Liver transplantation is a successful, long-term therapeutic option but is limited by scarcity of donor livers and chronic immunosuppression; making iPSC-based cell therapy an attractive prospect. As part of this project, we plan to generate iPSCs from hemophilic patients that will then be genetically corrected by inserting DNA capable of making FIX. After validation for correction, we will then differentiate these iPSCs into liver cells that can be transplanted into our mouse model of hemophilia that is capable of accepting human hepatocytes and allowing their proliferation. These mice exhibit disease symptoms similar to human patients and we propose that by injecting our corrected liver cells they will exhibit normal clotting as measured by various biochemical and physiological assays. If successful, this will provide a long-term cure for hemophilia and other liver diseases.

Statement of Benefit to California: 

Generation of iPSCs from adult cells unlocked the potential of tissue engineering, replacement and cell transplant therapies to cure a host of debilitating diseases without the ethical concerns of working with embryos or the practical problems of immune-rejection. We aim to develop a POC for a novel cell- and gene-therapy based approach towards the treatment of hemophilia B. In addition to the obvious and direct benefit to the affected patients and families by providing a potential long-term cure; the successful development of our proposal will serve as a POC for moving other iPSC-based therapies to the clinic. Our proposal also has the potential to treat a host of other hepatic diseases like alpha-1-antitrypsin deficiency, Wilson’s disease, hereditary hypercholesterolemia, etc. These diseases have devastating effects on the patients in addition to the huge financial drain on the State in terms of the healthcare costs. There is a pressing need to find effective solutions to such chronic health problems in the current socio-economic climate. The work proposed here seeks to redress this by developing cures for diseases that, if left untreated, require substantial, prolonged medical expenditures and cause increased suffering to patients. Being global leaders in these technologies, we are ideally suited to this task, which will establish the state of California at the forefront of medical breakthroughs and strengthen its biomedical/biotechnology industries.

iPSC-derived Hepatocytes as Platforms for Research in Viral Hepatitis and Non-alcoholic Steatohepatitis

Grant Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06563
Investigator: 
ICOC Funds Committed: 
$865 370
Disease Focus: 
Infectious Disease
Liver Disease
Metabolic Disorders
Human Stem Cell Use: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

Hepatitis C and fatty liver disease are the two most common liver diseases in California. Individuals from different backgrounds are susceptible to these liver diseases, but they have unique genetic profiles that may influence the severity of disease and the response to specific therapies. Technology now makes it possible to generate stem cells from a person’s own skin. These cells can subsequently be used to generate liver cells identical to those from the original donor. Using this approach, scientists can perform research directly on an individual’s own liver cells to identify features that make the cells susceptible or resistant to disease and drug therapy. In this project, the research team will collect blood and skin tissue from people with liver disease and from healthy control subjects. The donated tissues will be placed in a "bank" for the production of stem cells. The overall goal is for the donated cells to be made available to scientists who will convert them to liver cells, and then carefully study them to learn more about liver disease. Research such as this is extremely valuable because it allows patients and volunteers to make a very personal contribution to the understanding of liver disease. The materials donated to this tissue "bank" will be a resource to the scientific community for many years.

Statement of Benefit to California: 

Hepatitis C and fatty liver disease are the two most common liver diseases affecting the citizens of California. Together they afflict one in every 12 people in the state and kill roughly 4,000 state residents each year. Researchers in California are actively seeking new information about the causes of and treatments for liver disease; their progress will be greatly accelerated by the opportunity to directly study the biology of diseased patients. The goal of this project is to build a "bank" of stem cells from local patients with liver disease. Patient donors will come from many different backgrounds, reflecting the great diversity of California. The bank, once established, will be a tremendous resource for medical research because the banked cells will be renewable and made available to the entire research community. Banked stem cells will enable researchers to study the genetics and biology of liver disease and to test new therapies. Importantly, they will give researchers an opportunity to study liver disease in its most important context - the affected patient. The research made possible through this effort will greatly enhance our understanding of liver disease; this will in turn reduce the negative impact of liver disease on the health and well-being of California residents.

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