Circulating hematopoietic stem cells serve as novel targets for in utero gene therapy

Abstract

ABSTRACT In utero gene therapy has been proposed as a method for permanent correction of somatic disorders that affect the hematopoietic system before disease initiation (1, 2). However, clinical trials using transplantation of allogenic fetal liver, bone marrow, or adult stem cells have been unsuccessful, largely due to the failure of sustained hematopoietic reconstitution in fetal recipients (3). Here, we reveal that retroviral transduction of unique repopulating stem cells found in the human fetal circulation is superior to full‐gestation cord blood or adult sources. In contrast to postnatal human stem cells, the fetal circulation is highly enriched for actively cycling blood stem cells, thereby forming the basis for enhanced transduction. Our findings indicate that active, transducible hematopoietic reconstituting cells are present in the circulation of the human fetus and that they represent novel target cells for future in utero gene therapy trials using autologous transplantation.