Placental drug delivery for treatment of congenital hematopoietic disorders

Abstract

ObjectiveThe success of in utero hematopoietic cell transplantation (IUHCTx) hinges on successful conditioning strategies of the host to overcome barriers to engraftment. The "space" barrier is a reflection of a finite number of hematopoietic stem cell (HSC) niches within the host. Independent of the number of donor HSCs transplanted, engraftment is frequently low. By conditioning fetal mice using a monoclonal antibody against the c-kit receptor (ACK2) found on HSCs, we can effectively increase space for donor HSC engraftment. We questioned whether simple placental injection of ACK2 early in gestation could effectively deplete host HSCs within the fetal liver and neonatal bone marrow. MethodsIn this set of experiments, we injected mice with ACK2 (5μg/fetus) or PBS at E11.5–12.5 and harvested the fetal liver at 2 and 4days and the neonatal bone marrow at 7days following injection. Survival and total number of HSCs within the fetal liver or bone marrow were quantified and compared. ResultsSurvival between the treated and control group was similar (73% and 71%, respectively). The total number of HSCs within the fetal liver was not significantly lower following ACK2 treatment compared to PBS injected fetuses at 2days but was by 4days. Additionally, ACK2 resulted in a significant reduction in the number of HSCs within neonatal mice 7days after treatment. ConclusionSurvival following placental ACK2 injection is comparable to control animals and provides a simple non-invasive strategy to deliver ACK2 into the fetal circulation which successfully depletes the host HSCs.