In this reporting period we have conducted multiple analyses and successfully demonstrated therapeutic efficacy of placenta-derived stem cells (PDSCs) in all three proposed congenital metabolic disease model animals.
A lysosome disease model Idua deficient mouse was used to test therapeutic efficacy of the PDSC for Hurler disease. We demonstrated that the primary PDSCs express IDUA mRNA without in vitro manipulations. The IDUA gene and protein expressions are equivalent or higher levels than human hepatocytes. These data indicate that the primary PDSC is a suitable alternative cell source for the cell replacement therapy, hepatocyte transplantation. PDSC transplanted disease animals demonstrated increase of IDUA enzyme activity in the liver, lung and brain. Micro CT examination on the facial bone indicated that the PDSC treatment significantly improved the disease phenotype. The efficacy of PDSC transplantation was also assessed in animal models of Maple Syrup Urine disease (MSUD) and ornithine transcarbamylase deficiency (OTC). Five of 6 PDSC treated MSUD animals survived more than 100 days while all untreated MSUD animals died before 28 days of age. PDSC treatment also improved OTC disease phenotype and rescue the animals from transiently overdosed ammonia challenge. These data indicate that our approach to target the largest internal organ, the liver, to treat both systemic and liver specific congenital metabolic disorders is reasonable and efficient.
In conclusion, we successfully demonstrated that the therapeutic efficacy of human placenta-derived stem cell transplantation with all three congenital metabolic diseases murine models. Additional experiments and further detailed analyses are necessary to conduct statistic validations and to define the therapeutic mechanisms.