Y4 / NCE
The overall goal of this early translational research is to demonstrate the therapeutic efficacy of amniotic epithelial cells (AECs), a type of placental stem cells. AECs possess multilineage differentiation capability, low immunogenicity, and no tumorigenicity. In this project, we focused on testing the ability of these cells to treat animal models of three congenital metabolic disorders: mucopolysaccharidosis type1 (MPS-1), maple syrup urine disease (MSUD), and ornithine transcarbamylase deficiency (OTCD). Currently, there are no definitive therapies for these disorders. First, we evaluated the enzyme profile of AECs to determine whether they are suitable for treating each congenital metabolic disorder. We found that primary AECs possess the necessary enzymes to compensate for deficiencies in MPS-1 and MSUD. While primary AECs do not have ornithine transcarbamylase (OTC) enzyme activity to compensate for the deficiency in OTCD, they can acquire OTC gene expression after induction of hepatic differentiation. We utilized disease model mice to test the in vivo therapeutic efficacy for each disease. Human AECs (hAECs) transplanted into the livers of these mice improved disease phenotypes in all three mouse models. In the mouse model of MPS-1, the cell therapy improved not only the enzyme activity in the liver but also bone morphology and neural function. hAEC-treated MSUD mice survived more than 100 days, compared to control mice that only survived up to 30 days. We also successfully demonstrated improvement of the disease phenotype in the OTCD model mice. After transplantation, hAECs differentiated and acquired OTC enzyme activity in their mitochondria. Through a unique therapeutic mechanism, hAECs transferred these functional mitochondria to diseased mouse hepatocytes via tunneling nanotubes. In conclusion, we have successfully demonstrated the therapeutic efficacy of hAEC therapy for three congenital metabolic disorders. We are eager to move forward with our research in order to bring this promising stem cell therapy to patients with unmet medical needs.