In Utero Hematopoietic Stem Cell Transplantation: Progress toward Clinical Application

Abstract

In utero hematopoietic stem cell transplantation (IUHCT) is a potential therapeutic alternative to postnatal hematopoietic stem cell transplantation (HSCT) for congenital hematologic disorders that can be diagnosed early in gestation and can be cured by HSCT. The rationale is to take advantage of normal events during hematopoietic and immunologic ontogeny to facilitate allogeneic hematopoietic engraftment. Although the rationale remains compelling, IUHCT has not yet achieved its clinical potential. Achieving therapeutic levels of engraftment by IUHCT alone remains challenging. However, considerable experimental progress has been made toward the clinical strategy of using IUHCT to induce donor-specific tolerance to facilitate a relatively nontoxic postnatal HSCT. Because donor specific tolerance induction requires relatively minimal engraftment, this strategy may hold the key to broad clinical application of IUHCT in the near future.

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

“…Since the seminal experiments of Billingham, Brent, and Medawar (1), animal models of in utero hematopoietic cell transplantation (IUHCTx) have shown that the fetal environment offers considerable advantages for the success of stem cell transplantation (reviewed in ref. 2). In the mouse model, fetal mice can be tolerized to fully allogeneic stem cells without any immunosuppression (3,4).…”

Fetal Liver Cells Transplanted in Utero Rescue the Osteopetrotic Phenotype in the oc/oc Mouse

“…Still, the risk of graft versus host disease is not completely ruled out by the IUT approach and could be a concern for human studies, although we have not experienced this adverse effect in our mice and its occurrence in the 50 reported human trials was not high. 13 In the present work, we compare the results obtained with fetal liver cells to those previously obtained with whole adult bone marrow. We want to emphasize that, although performed sequentially, the two set of experiments with the two different kinds of donor cells used the same strain and were evaluated in an identical way, thus making the comparison meaningful.…”

“…23 On the other hand, at variance with primary immunodeficiency, whose symptoms do not develop before birth, osteopetrosis would greatly benefit from IUT and, even if only partial engraftment is obtained, the patients could still be treated with postnatal transplantation with minimal ablation using cells from the same donor, as suggested by other groups. 13 An additional unexpected finding was that, even with transplants that are apparently totally successful, sclerotic bone occurs in a highly localized, random regions, including microscopic regions of sclerotic bone associated with malocclusion. This suggests that, at least in mice, osteoclast differentiation reflects mainly cells from local colonies of precursors, so that clonal variation can cause patches of sclerotic bone in animals rescued by intrauterine transplant that have grossly normal skeletons.…”

“…Indeed, despite the strong rationale for IUT, there have been difficulties in achieving permanent engraftment of donor cells. 13 On the other hand, ethical use of human fetal cells should be achievable with suitable safeguards that may be a good source for the treatment of human ARO, if proven useful in animal models. Here we show that enzymatically disaggregated fetal liver cells can cure a high proportion of oc/oc mice when injected in utero.…”

Fetal Gene Therapy

“…Indeed, fetal transfusions and in utero stem cell-based therapies have now been performed clinically by numerous investigators for decades, using a variety of protocols, in efforts to treat patients with a number of different diseases [61,62]. While the stem cell trials have thus far only proven clinically successful in patients with immunodeficiencies, they have also demonstrated that accessing the early gestational human fetus multiple times poses minimal risks with modern imaging and ultrasound-guided delivery procedures [63]. Furthermore, it is important to note that experience and knowledge gained from studies performed in the fetal sheep model were used to design and perform the first curative human in utero transplantation for X-SCID [64], highlighting the value of the fetal sheep model for not only developing clinically viable methodology, but also for predicting clinical outcome.…”