In utero therapy for congenital disorders using amniotic fluid stem cells

Abstract

Congenital diseases are responsible for over a third of all pediatric hospital admissions. Advances in prenatal screening and molecular diagnosis have allowed the detection of many life-threatening genetic diseases early in gestation. In utero transplantation (IUT) with stem cells could cure affected fetuses but so far in humans, successful IUT using allogeneic hematopoietic stem cells (HSCs), has been limited to fetuses with severe immunologic defects and more recently IUT with allogeneic mesenchymal stem cell transplantation, has improved phenotype in osteogenesis imperfecta. The options of preemptive treatment of congenital diseases in utero by stem cell or gene therapy changes the perspective of congenital diseases since it may avoid the need for postnatal treatment and reduce future costs. Amniotic fluid stem (AFS) cells have been isolated and characterized in human, mice, rodents, rabbit, and sheep and are a potential source of cells for therapeutic applications in disorders for treatment prenatally or postnatally. Gene transfer to the cells with long-term transgenic protein expression is feasible. Recently, pre-clinical autologous transplantation of transduced cells has been achieved in fetal sheep using minimally invasive ultrasound guided injection techniques. Clinically relevant levels of transgenic protein were expressed in the blood of transplanted lambs for at least 6 months. The cells have also demonstrated the potential of repair in a range of pre-clinical disease models such as neurological disorders, tracheal repair, bladder injury, and diaphragmatic hernia repair in neonates or adults. These results have been encouraging, and bring personalized tissue engineering for prenatal treatment of genetic disorders closer to the clinic.

Antisense oligonucleotides delivered to the amniotic cavityin uteromodulate gene expression in the postnatal mouse

“…Injection into the amniotic cavity is likely to have as favorable a benefit/risk balance as amniocentesis, a diagnostic test involving removal of amniotic fluid, which carries a low miscarriage rate of ∼1 in 1000 (0.11%) (40). In utero therapies involving delivery of reagents to the amniotic cavity are not common but the approach is under increasing consideration as new promising therapeutic interventions become available for the treatment of disorders in early development (4,41–43). …”

“…Thus, model systems that can define safe and effective therapeutic strategies are needed. In utero stem-cell or gene therapies are currently being explored for the treatment of a limited number of diseases (4–6). However, testing of pharmacologic agents in utero has been largely unexplored.…”

Osteogenic differentiation of amniotic fluid mesenchymal stromal cells and their bone regeneration potential

“…These important features, together with the high proliferation rate, ease of retrieval and more stable profile, provide a convincing proofofprinciple for potential autologous application of AFMSCs for bone regeneration in perinatal applications [57] . Furthermore, a bank of such cells is achievable and may in the future provide a plentiful source for autologous therapy in adulthood as well as for transplantation into HLA matched recipients.…”

Stem cells from amniotic fluid – Potential for regenerative medicine

“…The IUT of AFSCs would involve harvesting the cells from the AF, in vitro gene therapy to correct the genetic defect and transplantation back to the donor foetus. Such a combined autologous stem cellegene transfer approach would also address some of the risks associated with administering gene therapy directly to the foetus (in utero gene therapy; IUGT) [31]. The possibility of performing in vitro gene transfer to harvested ASFCs would allow cells to be checked for insertional mutagenesis prior to transplantation, and it would obviate the risk of germ-line transmission of transgenes.…”