In Utero Bone Marrow Stem Cell Transplantation

Researchers at UCSF Medical Center have long been interested in the fetus as a recipient of bone marrow stem cells because early in gestation the fetus does not reject donor cells. The Pediatric BMT Program is recognized worldwide as a leader in this field. Based on research in both mouse and non-human primate models, and in conjunction with the UCSF Pediatric Clinical Research Center, we offer in utero bone marrow stem cell transplants using cells from a parent, for fetuses who have been diagnosed with severe combined immunodeficiency disease (SCID). This novel approach will someday permit infants, whose diseases are diagnosed while still in the womb, to be born with no evidence of their disease.

Animal models

Results of studies of in utero bone marrow stem cell transplantation in mice, sheep, cats and non-human primates make it clear that transplantation during the first trimester or early second trimester is essential to avoid rejection. Also, both fetal liver and adult bone marrow can successfully engraft. Unfortunately, a consistent finding in those models (mice, sheep, and monkeys) in which the recipient's hematopoietic system is intact (i.e., in which there is no stem cell or progenitor cell defect) has been a low percent (often <1%) of engrafted donor cells, inadequate to cure most candidate diseases.

Human experience

There have been over 40 in utero bone marrow stem cell transplants in humans. Fetal liver was first used successfully for a fetus with the bare lymphocyte syndrome. Subsequent in utero transplants have used fetal liver for alpha-thalassemia and thalassemia major, sickle cell anemia, Hurler’s disease and Nieman-Pick disease. While there has been evidence of engraftment in some of these transplants, there has been no clinical benefit. Parental adult marrow has engrafted in two fetuses with alpha-thalassemia and several fetuses with Severe Combined Immunodeficiency Disease (SCID), but only the children with SCID have benefited clinically. The low percent of engrafted donor cells is the greatest limitation to using in utero stem cell transplantation to treat the majority of inherited diseases in which there is no inherent survival advantage for donor bone marrow stem cells or committed progenitors.

The UCSF Pediatric BMT Program has performed three in utero transplants. Our first transplant was in a fetus diagnosed with alpha-thalassemia and transplanted at 18 menstrual weeks. The marrow was T-cell depleted and the cells were injected intraperitoneally into the fetus without any complications. Fetal blood samples were obtained at 24 menstrual weeks with no evidence of engraftment in the fetal blood, and a therapeutic abortion was performed. Upon examination of fetal tissue, female cells could be identified in this male fetus, indicating engraftment of maternal marrow. Our second in utero transplant was done at 20 menstrual weeks in a fetus diagnosed with SCID. No maternal cells were detected in the fetal blood either pre- or post-transplant (at 24 weeks), and the family elected to have a therapeutic abortion; an autopsy was refused. Our third in utero transplant was in a fetus with Chediak-Higashi disease. The transplant was done at 19 menstrual weeks and the family elected to continue the pregnancy so that no testing was conducted until the child was born at term. The child was evaluated at 1,3 and 6 months of age for evidence of maternal cells with no evidence of engraftment. She ultimately underwent a successful BMT at 12 months of age.

Eligibility for in utero BMT

• Diagnosis of an affected fetus with SCID in which the genetic defect is known (with some exceptions).
• Transplant must be performed by menstrual age less than 15 weeks (with the exception of selected SCID at less than 22 menstrual weeks).
• Parents have decided to continue the pregnancy to term.
• Donor bone marrow stem cells are available.
• No HLA matched sibling is available.