Generation of hepatic cell from placental stem cell for congenital metabolic disorders

Generation of hepatic cell from placental stem cell for congenital metabolic disorders

Funding Type: 
Early Translational III
Grant Number: 
TR3-05488
Approved funds: 
$1,750,375
Disease Focus: 
Liver Disease
Pediatrics
Stem Cell Use: 
Adult Stem Cell
Status: 
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.
Progress Report: 

Year 1

We took human amniotic epithelial cells (hAECs) from placentae and isolated the cells with the enzyme activities that are lacking in three inherited metabolic disorders: mucopolysaccharidosis type I (MSP I, or Hurler syndrome), maple syrup urine disease and ornithine transcarbamylase deficiency (OTC). By transplanting these enzymatically-active cells into mice, we demonstrated an effective treatment for these disorders. Our group and others have demonstrated that hAECs possess unique stem cell-like qualities, such as the ability to differentiate. More importantly, hAECs are genetically stable and therefore don’t form tumors upon transplantation in mice and humans. During the first year of the project, we identified markers on the surface of hAECs that indicate the presence of the genes that code for the desired enzymes. We successfully established colonies of mice with each of the three metabolic disorders and defined the protocols for the radiological and biochemical tests, or assays. We also performed several hAEC transplantations to mice with MSP I. The first case of hAEC transplantation demonstrated a very promising result: the pathologic protein concentration in the urine of the treated MSP I mouse was dramatically decreased. We will confirm this result by investigating it further in more mice. As proposed, we have also started building a small-scale bio-bank of hAECs from 24 placentae. These hAECs will be used to determine whether hAECs retain their therapeutic potential after cryopreservation, or freezing.

© 2013 California Institute for Regenerative Medicine