USA Surgery Today

In the not too distant future it may be possible to adequately diagnose and treat a much broader array of genetic disease in the fetus. Molecular biology has experienced dramatic advances in the past several years with high-throughput techniques such as proteomics and DNA microarray technology. When coupled with information derived from the human genome project, it is conceivable that many if not most human genetic diseases will diagnosed from a miniscule sampling of fetal DNA. Currently, it is possible to detect the presence of nucleated fetal cells in the blood of pregnant woman. This could provide a ready source of fetal DNA for potential prenatal genetic screening. Much like the new knowledge of fetal anatomic disease gained through prenatal US, the human genome project and high-throughput screening technologies will provide new opportunities for molecular fetal therapy.

The paradigm of fetal therapy thus far discussed, correction of a fetal abnormality prior to the onset of perinatal morbidity, remains the impetus for developing molecular strategies. There are several additional potential biologic advantages to prenatal stem cell therapy. It is known from postnatal work that, for cell transplantation to work, a regenerative stimulus and competitive advantage must exist for successful cell engraftment and expansion (127:Avapro). In consideration of fetal cell therapy, the ontogeny of fetal organogenesis may facilitate the engraftment and competitive expansion of “normal” donor cells by providing an expanded niche (8:Avapro). Perhaps more important may be the concept that fetal tolerance to previously foreign antigen could be induced. Any cellular therapy, much like whole organ transplantation is associated with host foreign antigen recognition and therefore would require either immunosuppressive therapy as for whole organ transplantation, or a strategy of tolerance induction (127). As the early gestation fetal immune system undergoes the developmental process of self-recognition, foreign cells and proteins introduced via fetal therapy could undergo tolerogenic incorporation for self-recognition (8).

Early experimental work and a belief in the principles of fetal tolerance and stem cell niche expansion in the developing fetus support the idea of replacing either cell or gene deficits for many human diseases (9). The best and only success story for human fetal stem cell therapy to date is for X-linked severe combined immunodeficiency (X-SCID) (128:Avapro). Successful in utero hematopoietic stem cell transplantation has provided proof of principle for prenatal stem cell therapy. Results in the few successfully corrected fetuses have at best, however, been comparable to postnatal transplantation. All other target diseases, including hemoglobinopathies and inborn errors of metabolism have failed thus far. These results taken together speak to both the potential and the difficulties of in utero stem cell therapy. In the case of X-SCID, it was learned that a distinct competitive advantage needs to exist for donor cell success. For each potential target disease, questions must be asked as to what level of engraftment of donor cells would be necessary to achieve phenotypic correction, and does a distinct and robust survival advantage exist for metabolically correct donor cells?:Avapro

In contradistinction to the experience with fetal stem cell transplantation, fetal gene therapy remains far from clinical application. Despite the appeal of gene therapy for the targeted replacement of a single deficient gene with propagation of that “new” gene to all progeny, the potential advantages of this approach in the fetus also speak to the current prohibitive hurdles. Given the current use of modified viral vectors for efficient gene delivery, safety concerns include insertional mutagenesis, germline transmission, potential for tolerance to viral antigens, and alterations in other normal fetal developmental processes (8,129,130). The challenge is to develop safe and effective gene transfer techniques that will allow long-term and tissue-specific regulated gene expression (131:Avapro). Perhaps in the future a combined approach of ex vivo gene therapy for the genetic correction of prospectively isolated fetal stem cells with subsequent reintroduction into the expanding fetal milieu would allow for exploitation of both of these approaches. There is little doubt that future clinical promise of fetal molecular therapy remains an appealing concept.