Gene transfer into fetal baboon hematopoietic progenitor cells

We studied hematopoietic progenitors from fetal baboon blood, marrow, and liver at four time points (125, 140, 160, and 175 days) during the third trimester (gestation approximately 180 days) to determine if fetal baboons might be an appropriate model for in utero gene therapy of hematopoietic stem cells (HSCs). Cells were studied for expression of CD34, CD33, CD38, and HLA-DR, for progenitor content in colony-forming cell assays, and for susceptibility of CD34+ progenitors to retrovirus-mediated gene transfer. Throughout the third trimester, the frequency of CD34+ progenitors in blood and marrow appears to remain unchanged at approximately 0.6 and 5.0%, respectively. In liver, progenitors progressively decrease to undetectable levels by day 175. The proportion of fetal baboon bone marrow and liver CD34+ cells expressing CD38 and HLA-DR appears to increase with increasing fetal age, similar to changes reported for human cord blood CD34+ cells. In fetal baboon blood the proportion of CD34+ cells expressing CD33 appears to decrease with increasing gestational age, also similar to changes reported for human cord blood cells. Progenitors from human cord blood and baboon fetal tissues were similarly susceptible to transduction by the gibbon ape leukemia pseudotyped retroviral vector LAPSN(PG13) containing the genes for human placental alkaline phosphatase (AP) and the bacterial neomycin phosphotransferase (neo). Fetal baboon and human hematopoietic progenitor cells undergo similar phenotypic changes during the third trimester of fetal development and are similarly susceptible to retrovirus-mediated gene transfer. The fetal baboon may be a model in which approaches to mobilization and gene transfer into fetal HSCs can be studied.