Fetoscopic versus Ultrasound-Guided Intravascular Delivery of Maternal Bone Marrow Cells in Fetal Macaques: A Technical Model for Intrauterine Haemopoietic Cell Transplantation

Abstract

Introduction: Significant limitations with existing treatments for major haemoglobinopathies motivate the development of effective intrauterine therapy. We assessed the feasibility of fetoscopic and ultrasound-guided intrauterine haemopoietic cell transplantation (IUHCT) in macaque fetuses in early gestation when haemopoietic and immunological ontogeny is anticipated to enable long-term donor cell engraftment. Material and Methods: Fluorescent-labelled bone marrow-derived mononuclear cells from 10 pregnant Macaca fascicularis were injected into their fetuses at E71–114 (18.9–170.0E+6 cells/fetus) by fetoscopic intravenous (n = 7) or ultrasound (US)-guided intracardiac injections, with sacrifice at 24 h to examine donor-cell distribution. Results: Operating times ranged from 35 to 118 min. Chorionic membrane tenting and intrachorionic haemorrhage were observed only with fetoscopy (n = 2). Labelled cells were stereoscopically visualised in lung, spleen, liver, and placenta. Donor-cell chimerism was highest in liver, spleen, and heart by flow cytometry, placenta by unique polymorphism qPCR, and was undetected in blood. Chimerism was 2–3 log-fold lower in individual organs by qPCR than by flow cytometry. Discussion: Both fetoscopic and US-guided IUHCT were technically feasible, but fetoscopy caused more intraoperative complications in our pilot series. The discrepancy in chimerism detection predicts the challenges in long-term surveillance of donor-cell chimerism. Further studies of long-term outcomes in the non-human primate are valuable for the development of clinical protocols for IUHCT.