In this reporting period we have conducted multiple analyses and accomplished several tasks. First, we 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 systemic congenital metabolic diseases. We demonstrated that unfractionated PDSCs express IDUA mRNA and protein at equivalent or higher levels than human hepatocytes. PDSC transplanted mice demonstrated a 15.1% and 32.5% increase of IDUA enzyme activity in the liver and lung, respectively. Interestingly, brain IDUA activity drastically improved (96.5%). We also established quantitative and qualitative bone mass evaluation methods using micro CT. Although the therapeutic efficacy on the bone phenotype of IDUA mouse was limited, the recipient demonstrated slight improvement. This data indicated that our approach to target the largest internal organ, the liver, to treat systemic metabolic disorders was reasonable and efficient. We will further study the optimal condition of PDSC transplantation and the mechanism of cell therapy.
Our single cell gene expression analysis data indicated that the PDSC contains BCKDHa expressing cells. Using an intermediate Maple Syrup Urine disease model mouse, we conducted ultrasound guided cell injections to visualize transplanted cell distribution.
Previous data indicated that primary PDSCs do not express the OTC gene. We conducted unfractionated PDSC transplantation into Spf/Ash mouse, which is a disease model with OTC deficiency. The urine proteomic analysis data indicated that the PDSC transplantation clearly improved the OTC phenotype. We will further increase the number of recipient mice as well as test different dosages and frequencies of cell transplantation.
In conclusion, the project has been progressing very well and has demonstrated promising data in treating congenic metabolic disorder patients with placenta derived stem cells.