In utero transplantation: baby steps towards an effective therapy

Abstract

In utero transplantation (IUT) offers the potential to treat a large number of diseases by transplantation of healthy cells into a fetus with a birth defect. Prenatal diagnosis is feasible for many diseases prior to the full development of the fetal immune system offering the opportunity to introduce foreign cells and antigens into the developing fetus. At least 45 cases of IUT have been performed for a variety of diseases. IUT has successfully treated severe combined immunodeficiency and there are indications that it may be effective in treating some nonhematopoietic diseases. However, many diseases remain resistant to fetal therapy owing to the low levels of chimerism that can be achieved. Promising efforts to improve the levels of engraftment are focusing on optimizing the graft and developing donor-specific tolerance in the fetal recipient. Mounting evidence suggests that donor T cells can aid in achieving clinically significant levels of chimerism. The use of fetal donor cells may also offer some benefit. Animal experiments suggest that even low-level chimerism can lead to tolerance, which can be exploited by booster transplants in the neonate. Continued research appears likely to succeed in developing IUT into an effective form of therapy for a variety of diseases.

Fetal Liver-Derived Mesenchymal Stem Cell Engraftment After Allogeneic In Utero Transplantation into Rabbits

“…However, due to ethical considerations, special care must be taken to assure safety and efficacy in fetal interventions before clinical applications can be initiated. In fact, in utero cell transplantation has already been attempted for immunodeficiencies, hemoglobinopathies, enzyme storage disorders, and other inherited diseases such as hemophilia A [1]. For example, prenatal tolerance induction has been a main goal of in utero hematopoietic stem cell transplantation, to facilitate postnatal cellular transplantation [2,3].…”

Immunoresponse against the transgene limits hematopoietic engraftment of mice transplanted in utero with virally transduced fetal liver

“…2,8 Moreover, T cells showing TCR rearrangement have been observed in human FL in the 13th week of gestation, 26 and FL NK cells and fetal T cells have been demonstrated alloreactive in vitro. [27][28][29] These lines of evidence could indicate the engraftment failure of FL hematopoietic cells transplanted in utero in allogeneic recipients.…”

“…In utero transplantation in human fetuses has been successful only in immunodeficient patients. 8 Evidence of in utero engraftment of allogeneic cells has been reported in different animal models and in humans. 9 However, the recently described failure of long-term chimerism after IUHCT of allogeneic grafts in mouse models 10 suggests the immunocompetent status of the fetus.…”

“…4,11 Although the principal sources of hematopoietic cells for transplantation in humans are adult BM, mobilized peripheral blood and umbilical cord blood, fetal liver (FL) hematopoietic progenitors are a good alternative for IUHCT because both recipient and graft coincide in developmental stage. 8 In addition, the expression profiles of adhesion molecules in FL-HSCs (FL-HSCs) 12 could confer cells improved homing and engraftment capacities over adult HSCs in response to IUHCT. In a gene therapy context, recent studies have shown that FL-HSCs proliferate more actively than adult BM HSCs 13,14 and are differentially regulated by transcription factors.…”

Early chimerism threshold predicts sustained engraftment and NK-cell tolerance in prenatal allogeneic chimeras

“…In the absence of immunosuppression, only microchimerism has been achieved in human fetal recipients or nonhuman primate models of IUHCT. [1][2][3][4][5][6] These levels are too low for the correction of most diseases and have not been demonstrated to predict tolerance. The reasons for this failure are unclear and reflect a limited understanding of the engraftment barriers involved in clinical IUHCT.…”