The unifying aim of the research is to develop prenatal treatment of severe and life-threatening disorders using gene and cellular therapy, and to investigate the efficacy, safety and ethical issues of such treatment. This work is internationally competitive and only a few groups in the world are working in the area. Under the MRC Programme grant, we have developed new ultrasound guided injection techniques to deliver gene therapy vectors to fetal organs such as the trachea to target the airways, the stomach to target the small bowel, the thorax to target the fetal intercostal muscles and diaphragm, the muscle and the brain. Using these techniques we showed significant levels of reporter gene expression in the fetal airways which might be used for prenatal treatment of cystic fibrosis. In collaboration with Dr Simon Waddington (Senior Research Fellow, Department of Haematology Haemophilia Centre and Haemostasis Unit, Royal Free and University College Medical School) we have studied a variety of new and improved vectors and agents designed to achieve long term gene transfer. For prenatal treatment of haemophilia we also showed therapeutic levels of transgenic human Factor IX protein (hFIX) can be achieved in the blood. No antibodies to the transgenic protein could be detected after early gestation injection of adenovirus, a vector that only gives short term expression. Using an adeno-associated virus (AAV) and in collaboration with Dr Amit Nathwani, Senior Lecturer in Dept Haematology at UCL we showed for the first time in a large animal, that long term expression of hFIX could be achieved in the blood of neonates born after fetal gene therapy using ultrasound guided intraperitoneal injection. This vector is currently being evaluated in an NHS funded clinical trial of AAV hFIX gene therapy treatment in adult haemophilia patients at UCL. In collaboration with Dr Simon Waddington (Senior Research Fellow, Department of Haematology Haemophilia Centre and Haemostasis Unit, Royal Free and University College Medical School) we have shown that the presence of maternal antibodies prevents gene transfer to the fetus.