Developmental candidate: hESC derived therapies for neonatal urea cycle defects

Funding Type: 
Early Translational I
Grant Number: 
TR1-01217
Investigator: 
ICOC Funds Committed: 
$0
Public Abstract: 
For severe liver diseases, transplantation is the only effective therapy. In California 750-800 liver transplants are performed annually, saving many lives but at a staggering cost: $300,000 for the first year plus $30,000 per patient per year, totaling over $440 million every year. Liver transplantation is limited by the supply of donor organs, especially livers suited to pediatric transplant. Urea cycle disorders (UCD) are severe diseases of newborns in which ammonia is not correctly metabolized in the liver. Ammonia accumulation rapidly leads to nerve damage and often death. Liver transplantation is currently the only cure. Because the livers of UCD patients are normal in all other functions, thus stem cell therapy could be a successful, minimally invasive, UCD treatment. There recently has been importance progress in developing stem cell therapy for cellular therapies for liver disease. Stem cell therapy for liver disease can be viewed as a platform technology. When the basic strategy fro engrafting new cells in the liver is achieved in a defined group of high-risk UCD patients, the resulting understanding would pave the way for much broader applications. We propose to generate mouse models of UCD from immunocompromised mice and use these disease models to demonstrate that human embryonic stem cells, developed in the lab into committed liver progenitor cells, can engraft into intact livers and function as liver cells. Implantation of committed progenitor cells will greatly reduce the risk of cancer (teratoma formation). To minimize transplant rejection we will build a bank of progenitor cells from different human embryonic stem cells lines developed by members of our team at [REDACTED], and assess tissue matching with normal human lymphocytes. We will use advanced imaging, developed by our team, to noninvasively track the engraftment of the human progenitor cells into the mouse liver. If embryonic stem cell-based cell therapies perform as anticipated in these dire diseases, they could be directed toward many conditions not necessarily perceived as liver disease. Hemophilia A and B are two examples of genetic diseases stemming from defective proteins produced by the liver that greatly affect quality of life. The liver is the site of LDL processing and a genetic mutation in the LDL receptor results in familial hypercholesterolemia, a disorder leading to early heart disease in 1 of 600 individuals. Repopulating patients’ diseased livers with stem cells carrying normal genes could cure these diseases. In the future, modifying the genes of stem cells before engrafting them into the liver could treat an even broader spectrum of liver disease, including hepatitis C. Furthermore, the technologies developed for monitoring the relevant events following stem cell implant in patient models could direct development of additional stem cell therapies.
Statement of Benefit to California: 
Our plan addresses important unmet medical needs for liver replacement surgery with new research to develop stem cell therapy that will be rapidly translated into patient treatment. For many severe liver diseases, transplantation is the only effective therapy. In California 750-800 liver transplants are performed annually-a great advance saving many lives but at a staggering cost: $300,000 for the first year plus $30,000 per patient each year for medications, totaling over $440 million every year. Liver transplantation is, however, limited by the supply of donor organs. Of the 20,000 patients awaiting surgery approximately 3,000 will die before a suitable liver becomes available. Other patients will not be viable candidates for transplant surgery. Long-term immunosuppression exacerbates other diseases and reduces life expectancy. This is especially true for pediatric liver transplant recipients, in which normal development is affected and long-term morbidities accumulate. Clearly there is a need for new therapies that are less invasive and more available and cost-effective. Rapid advances in stem cell shows true progress toward cellular therapies for liver disease. Stem cell therapy for liver disease can be viewed as a platform technology. When the basic strategy fro engrafting new cells in the liver is achieved in a defined group of high-risk patients the resulting understanding would pave the way for much broader applications. Infants with lethal genetic disorders of liver metabolism, called urea cycle defects, form one such patient population. They cannot properly metabolize dietary protein and suffer severe or lethal neurological damage. The affected child’s liver is otherwise normal, thus research indicates that partial liver replacement with cells derived from normal human embryonic stem cells (hESC) would be a viable therapy, if scientific hurdles can be cleared and the treatment shown to be safe and effective. If hESC-based cell therapies perform as anticipated in these dire diseases, they could be directed toward many conditions not necessarily perceived as liver disease. Hemophilia A and B are two examples of genetic diseases stemming from defective proteins produced by the liver that greatly affect quality of life. The liver is the site of LDL (bad cholesterol) processing and a genetic mutation in the LDL receptor results in familial hypercholesterolemia, a disorder leading to early heart disease in 1 of 600 individuals. Repopulating patients’ diseased livers with stem cells carrying normal genes could cure these diseases. In the future, modifying the genes of stem cells before engrafting them into the liver could treat an even broader spectrum of liver disease, including hepatitis C. Furthermore, the technologies developed for monitoring the relevant events following stem cell implant in patient models could direct development of additional stem cell therapies.

© 2013 California Institute for Regenerative Medicine