The potential of stem cell biology in regenerative medicine is vast; yet in each organ system, unlocking this potential will require a comprehensive, detailed approach unique to that system or organ. Our lab is dedicated to fully developing all aspects required to bring stem cell therapeutics from the laboratory to clinically useful therapies. We have developed a strategy using embryonic stem (ES) cells differentiated in the laboratory in such a way that that these cells successfully transplant into the liver tissue and function. This process could treat diseases where defective proteins are not made, or made improperly like Hemophilia A and B. Furthermore, if the resident stem cell of the liver can be replaced or augmented, these therapies might be long-term, or even lifelong.
However, the biggest roadblock to the clinical testing of these treatments is a proper mouse model, where the liver to be treated responds as a human liver would, when receiving the cell transplants. Only then we can track the human cellular transplant for an adequate duration, and have confidence that the cells are safe and durable.
We propose to develop a mouse model, a series of human embryonic stem cells, and strategic genetic changes to achieve the goal of possessing as nearly normal a “humanized” liver as possible. If we are successful in creating a mouse model with the described properties, it is likely that we will learn new information about stem cells in general that could have broader application to stem cell therapeutics in other organs while adding to the understanding of other liver diseases.
We believe this model could be produced within the time frame of the award. Our five-year plan would be to specialize in multiple applications where genetically modified stem cells could treat liver based disorders. With development of the model described here, one could follow up with a stem cell based strategy for the treatment of hepatitis C infection. Imagine if viral resistant cells could one day remodel the liver and clear Hepatitis C infection. This could be a one-time treatment for patients with Hepatitis C infection, which is a world wide pandemic. Such lofty goals for liver based stem cell therapeutics begin with a robust humanized liver model.
Liver Disease is the 12th leading cause of death in the United States. However, a strong case can be made that its impact is greater on the State of California than more prevalent diseases. The death rates are skewed such that the liver disease takes life in its prime. The rank is 7th between the ages of 35 to 45, and 4th between the ages of 45 to 55. Among Native Americans between the ages of 35 to 45 it is the second most common cause of death. Currently liver transplantation is the only viable therapy for life threatening liver diseases, but this modality is very expensive and available to only a fraction of those worldwide that need a transplant.
However, the greatest need that may one day be addressed by stem cell therapies is viral hepatitis. Outside the U.S, hepatitis B and C are worldwide pandemics, and these are diseases that affect urban and underprivileged populations disproportionately. Through stem cell technologies, the State of California has the opportunity to develop a cure for these slow killers. Now, there is a benefit California! Since these are chronic viral infections they are very difficult and extremely expensive to treat, even partially. The vast majority of the 350 million with hepatitis B and 170 million people with hepatitis C are in developing regions, and are not likely to benefit from future antiviral therapies and certainly cannot avail themselves to current medical regimens. Eighty percent of these infected individuals will eventually develop life threatening complication of the chronic infection such as cirrhosis, and liver cancer.
We are proposing that a stem cell, genetically engineered to be resistant to these viral particles, could become a one-time cure. For this promise to come to fruition, we must master the technologies to safely engraft Human Embryonic Stem Cell derivates into the liver for the diseases that can most directly be treated in this manner.