Fetal Therapy For Inborn Errors Of Metabolism Using
Selective Cell Transplantation
Inborn Errors Of Metabolism
Variations and abnormalities have been described for virtually
every known gene. Certain abnormalities with known devastating
consequences occur when gene expression (or non-expression) is
localized to a particular organ. In such instances, it may be
feasible to overcome the genetic defect by transplanting tissue or
organs that contain the normally functioning gene into the
defective host. Several candidate genetic abnormalities ideally
suited to this approach have been described, many of which are
categorized as inborn errors of metabolism. Tissue or organ
transplantation after birth usually requires some form of
recipient immunosuppression, which may be devastating to the host.
In addition, several of the genetic defects have an effect prior
to birth in the fetus or at birth before tissue replacement can
occur. Therefore, it would be advantageous to introduce normally
functioning tissue into the recipient prior to injury.
Most organ-specific genetic defects are only expressed after
organogenesis in the developing fetus. Furthermore, the effects of
certain organ-specific enzyme pathway genetic defects only become
injurious to the host late in development or after birth because
in utero, the placenta dialyses the fetal circulation. This
creates a therapeutic window during fetal development where an
intervention may correct a genetic defect prior to it affecting
the fetus. In addition, during the late first and second
trimester, this therapeutic window overlaps the time period when
the fetus is immunologically tolerant to foreign antigens,
presenting the ideal opportunity for tissue transplantation
without requiring immunosuppression.
The most simplistic fetal therapy protocol involves the
transplantation of normal cells into the affected fetal liver.
More complex therapies include the replacement of defective fetal
bone marrow with immature but normal fetal liver cells that
contain hematopoietic stem cells, or the introduction of viral
vectors used to insert normal genes into the defective fetal
genome. Such gene therapy is currently ongoing in our and other
experimental laboratories. Several human trials involving fetal
bone marrow replacement for genetic defects are currently ongoing
with moderate early success. Further research is aimed at the
induction of tolerance by cell transplantation during the fetal
period, which would allow for organ transplantation without
immunosuppression in the neonatal period.
Tolerance to fetal cell transplantation is currently under
investigation in our laboratory. The longevity of the tolerant
period and methods to extend this period as well as the ability to
induce tolerance in the fetus by cell transplantation that would
subsequently support whole organ transplantation in the postnatal
period is being investigated. This direction has particular
application in the field of xenotransplantation.
Several strategies have been proposed to increase the
transplanted cell mass. A two pronged approach to these
investigations is required. Firstly, a structured cellular
environment needs to be created using a biodegradable scaffold
that allows neovascularization of a large mass of transplanted
cells to recreate an organ-like complex attached to the omentum or
bowel mesentry. Such neo-organogenesis would comprise of donor
parenchymal cells maintained by a recipient non-parenchymal cell
structural network. The development of a biodegradable
microskeleton for this purpose is currently ongoing. Secondly, a
strategy for trophic support of the transplanted cell mass needs
to be developed. Such strategy should not only stimulate the cell
mass to rapidly increase in size, but should also stimulate
neovascularization of the cell mass.
By exploiting the immune "naïve" window in the fetus,
when there is no immune distinction between self and non-self,
cells which contain the missing gene may be placed in the
defective fetus without the need for immunosuppression. Such
transplantation would also occur prior to the need for functional
gene products within the fetus. Postnatally, these transplanted
cells would produce enough product to maintain normal or
near-normal functional levels. In addition, if the fetus has
become tolerant to the donor cells, but there is attrition of
these cells, a boost infusion of same-donor cells may be feasible
in the early neonatal period should the fetus have been made
tolerant by the initial transplant.
Fetal liver stem cells may induce tolerance which may preclude
booster doses postnatally. Such protocols have already been
successfully implemented in humans to replace defective bone
marrow. However, simultaneous cellular grafts have not been
investigated in detail. The emphasis in this work has been on the
development of chimerism within the immune system.
Our work is specifically directed at cellular fetal
transplantation to organ-specific inborn errors of metabolism
because we have all the tools necessary at our disposal. Once the
technique for correcting the defect is established in the
laboratory, the final step is to put it into clinical practice.
The method may also then be extended to other forms of inborn
errors in metabolism with minor modifications.