Liver Disease Team for development of novel tools and antiviral therapies from human embryonic and pluripotent stem cells

Funding Type: 
Disease Team Planning
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

The proposal is to develop a plan to integrate a multidisciplinary team of scientists diverse expertise required to commercialize a clinically-relevant product using stem cells within 4 years.

Our disease target is hepatitis C which is the leading cause of hepatic cancer and the primary reason for liver transplantation in the U.S. This infectious disease afflicts 170 million people worldwide and its’ incidence is projected to triple over the next 20 years so that it will kill more people worldwide than AIDS. At present, there is no suitable antiviral therapy for hepatitis C. One reason for this is the lack of a suitable model system to study hepatitis C infection and the effectiveness of potential antiviral agents in the laboratory. Humans and sub-human primates are the only species that infect with HCV. Hence, there are no cost-effective, natural animal models to study hepatitis. A laboratory model system must include hepatocytes (liver cells which are the target of HCV) which can be infected by HCV in the laboratory, HCV must actively grow in these hepatocytes and the infected hepatocytes must themselves grow or survive in the laboratory for long periods of time so that their response to antiviral drugs can be assessed.

At present, HCV infection is studied in hepatocytes isolated from livers that are donated for transplant but found to be unsuitable for clinical use. These livers come from a pool of donors of diverse ages, genders, health status and ethnic backgrounds and their overall quality can also be highly variable. Regardless of overall quality, it is unusual for hepatocytes to survive in a highly functional state for more than a week in the laboratory and this severely limits the development of anti-HCV therapies.

We propose to use stem cells to produce hepatocytes for use in a unique laboratory model of human liver tissue. Instead of using isolated hepatocytes as a model, we grow liver tissue in three dimensions (as in the body) using not only hepatocytes but other cells found in the liver as well. These 3D tissues maintain liver function over extended periods in the laboratory and thus allow for the assessment of the effects of chronic drug exposure (commercialized application). A previous grant collaboration between members of this proposed team has demonstrated that these 3D tissues can be infected with and replicate hepatitis viruses C and D.

Stem cell-derived hepatocytes have several potential advantages over adult donor liver-derived hepatocytes for this project including the elimination of the hepatocyte sourcing and quality issues. We have already produced 3D liver tissues using mouse stem cell-derived hepatocytes.

The proposed team has expertise in hepatitis, stem cells and commercialization of FDA-approved tissue-based therapeutics. New personnel will be recruited to fill gaps. Goals are to advance a new HCV antiviral into the clinic and market a human liver 3D tissue-based antiviral screening platform in 4 years.

Statement of Benefit to California: 

The incidence of hepatitis C (HCV) in the United States has been estimated at 1.8% [1], and more recently at 2.5% from a population-based sample of young women living in poorer neighborhoods in California [2], the state with the greatest number of HCV+ people. Computer modeling projects 165,900 deaths from chronic liver disease, 27,200 deaths from hepatocellular carcinoma, and $10.7 billion in direct medical expenditures for HCV from the year 2010 through 2019 [3]. During this period, HCV may lead to 720,700 years of de-compensated cirrhosis and hepatocellular carcinoma and to the loss of 1.83 million years of life in those younger than 65 at a societal cost of $21.3 and $54.2 billion, respectively [3]. HCV causes an estimated 8,000 to 10,000 deaths annually in the U.S. and accounts for 60 – 70 percent of chronic hepatitis cases, and 30 percent of cirrhosis, end-stage liver disease, and liver cancer cases. At least 75 percent of patients with acute hepatitis C ultimately develop chronic infection, and most of them have accompanying chronic liver disease. Liver failure from hepatitis C is the most common reason for a liver transplant. Currently, it is estimated there are about 170 million people worldwide who are infected with HCV, 4 million of those are in the United States.

The goal of this disease team planning proposal is the development of a human liver tissue model of HCV infection using liver cells derived from stem cells and to employ this model to advance new HCV antiviral therapies to the clinic. In addition to this direct benefit to the citizens of California, indirect benefits include development of novel core facilities and shared equipment resources, experienced collaborative research teams that can attract millions of dollars of additional funding to the state, spinout companies from new technology development, tax revenues and employment opportunities resulting from this new technology, new funding and spinout companies.

The program would also create a collaborative team spanning major liver transplant centers throughout California, facilitating patient access to treatments and the teams access to normal and diseased tissues and multiple clinical trial sites. {REDACTED} has been successful largely because of the strong biotechnology community in {REDACTED} with who {REDACTED} has partnered to develop and commercialize its products. These partnerships have brought millions of dollars of government grants to {REDACTED} as well as the promise of a growing, profitable tissue engineering and stem cell industry that will deliver innovative cell and tissue technologies to revolutionize patient care. There are few cities in the US that have the biotechnology infrastructure and collaborative environment that has enabled {REDACTED}’s success.

{REDACTED} received the 2007 Most Innovative New Product Award {REDACTED} for its first product, {REDACTED}. National press recognized our California company.