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, preclinical 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 preclinical 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.

Investigating Optimal Autologous Cellular Platforms for Prenatal or Perinatal Factor VIII Delivery to Treat Hemophilia A

“…These cells performed far better than MSC derived from adult BM with respect to FVIII production levels, both prior to and following transduction with an HSQ-encoding MMLV-based vector. Combined with their demonstrated ability to engraft and persist long-term in multiple tissues after prenatal delivery ( Shaw et al, 2011b , 2016 ; Yang et al, 2013 ; Subramaniam et al, 2018 ), AF-MSC could represent a viable autologous cellular platform for delivering a FVIII transgene in utero . However, the use of autologous gene-modified AF-MSC prenatally would not be trivial, given the length of time required for their transduction and subsequent in vitro expansion, and the limited temporal window during which in utero transplantation can be performed and immune tolerance to the exogenous transgene product induced ( Tran et al, 2001 ; Waddington et al, 2003 ; Porada et al, 2004 ; Colletti et al, 2008 ).…”

“…To perform prenatal autologous cell-based HA treatment requires a cell type that can safely be obtained from the fetus, gene-modified to constitutively express FVIII, expanded sufficiently in vitro , and returned to the fetus early enough in gestation to exploit the immunological advantages of prenatal intervention. For this reason, the first cells we considered were amniotic fluid-derived mesenchymal stromal cells (AF-MSC), which fulfill all of these criteria, can safely be obtained via amniocentesis, and are currently being explored for treating multiple diseases ( De Coppi et al, 2007 ; Steigman and Fauza, 2007 ; Antonucci et al, 2011 ; Bollini et al, 2011a , b ; Moorefield et al, 2011 ; Poloni et al, 2011 ; Shaw et al, 2011a , b ; Fernandes et al, 2012 ; Murphy and Atala, 2013 ; Yang et al, 2013 ; Brown et al, 2014 ; Ramachandra et al, 2014 ; Zani et al, 2014 ; Chang et al, 2015 ; Li et al, 2015 ; Mariotti et al, 2015 ; Lazzarini et al, 2016 ; Balbi et al, 2017 ; Kunisaki, 2018 ; Subramaniam et al, 2018 ).…”