IN-UTERO HEMATOPOIETIC STEM-CELL TRANSPLANTS FOR INHERITED DISEASES

Purpose: The treatment of choice for many inherited diseases is bone m arrow transplantation (BMT). Limitations to using marrow transplants f or inherited diseases include (a) the toxicity associated with high do ses of chemotherapy necessary to obtain engraftment; (b) the complicat ions associated with graft-versus-host disease (GVHD); (c) the fact th at only 20-25% of children will have a human leukocyte antigen (HLA)-m atched donor; and (d) the concern that, at least for some inherited di seases, significant organ damage, especially to the nervous system, ha s occurred by the time the child is diagnosed and evaluated for possib le BMT. In utero transplantation of hematopoietic stem cells (HSCs) of fers the possibility of overcoming many of these limitations. Patients and Methods: One of the biggest hurdles to a successful transplant is the ability of the recipient to reject the donor marrow. Except in pa tients with severe combined immunodeficiency disease (SCID), overcomin g this hurdle requires high doses of chemotherapy. Early in gestation, the fetus is significantly immunoincompetent. Before 14-15 weeks of g estation, the human fetus appears to be similar to a child with SCID i n its inability to reject allogeneic cells. Potential sources for HSCs are HLA-matched sibling marrow, fetal liver, parental bone marrow, an d cord blood. Results: With fetal liver, only cells from fetuses <10-1 2 weeks are acceptable because of the high risk of GVHD. With parental marrow, the cells must be T cell depleted in order to minimize the ri sk for GVHD. Problems in using fetal liver include the inability to ob tain sufficient numbers of cells and inadequate supplies of donor tiss ue. The source and supply of parental bone marrow is almost unlimited, but, because of the need for T-cell depletion, bone marrow from a par ent may have a lower engraftment rate in the child. Conclusions: Studi es in fetal murine and Rhesus models using fetal liver or T cell-deple ted bone marrow from adult animals suggest that engraftment can be suc cessfully obtained, providing the transplant is performed sufficiently early in gestation. To date, at least a dozen in utero human transpla nts have been attempted worldwide in fetuses diagnosed with a variety of inherited diseases. Because of the small number of transplanted fet uses and the variety of diseases and differing transplant conditions, it is difficult to draw any firm conclusions regarding ultimate effica cy of the procedure and its risks. However, it does appear that the ag e of gestation of the recipient, the dose of cells infused, and possib ly the route of administration of the HSCs will be critical factors in determining success rates for this approach. The successful applicati on of in utero transplantation would allow treatment of a variety of i nherited diseases early in gestation while eliminating many of the ris ks associated with conventional BMT.