Can we treat genetic blood disorders by transplantation of stem cells to the fetus? (360G-Wellcome-099083_Z_12_Z)

Congenital diseases such as blood disorders are responsible for over a third of all paediatric hospital admissions. In utero transplantation (IUT) could cure affected fetuses but so far in humans, successful IUT has been limited to fetuses with severe immunologic defects. The maternal immune system and a functionally developed fetal immune system are thought to be responsible. This could be overcome by the use of autologous cells. Autologous haematopoietic progenitors can be easily derived from amniotic fluid (AF). They can engraft long term into fetal sheep. IUT of genetically corrected autologous amniotic fluid stem cells (AFSCs) could be therapeutic strategy for the treatment of congenital disease like thalassaemia. Using a novel humanised mouse model of thalassaemia (CA), which closely mirrors human disease, I will study IUT with AFSCs from CA mice after gene correction with a lentivirus vector containing the beta-globin gene. I will first demonstrate engraftment of normal GFP+ mou se AFSCs into CA mutants. Then transplant gene corrected beta-thalassaemia CA mutant mouse AFSCs. The primary outcome measure is neonatal survival of homozygous CA mice. Secondary outcome measures will include stable correction of the severe anaemia. Finally I will study gene transfer to AFSCs from human pregnancies affected by Thalassaemia.