Novel fetal therapy

Abstract

The development of new treatments to reduce acute and chronic neonatal lung disease is a research priority. In Section One of this thesis, the novel approach of a candidate cell therapy is investigated as such a possible treatment. Human amnion epithelial cells (hAECs) - derived from term placentae – have pluripotent and anti-inflammatory properties that may offer hope for preterm lung disease. I use a previously validated fetal sheep model of ventilation-induced lung injury, whereby in utero ventilation produces many of the histological hallmarks of bronchopulmonary dysplasia (BPD) such as increased collagen and elastin deposition, arrested alveolarisation and pulmonary inflammation. I showed that the administration of undifferentiated human amnion epithelial cells to the preterm fetus mitigated this injury and restored developing alveoli. This proof-of-principle study offers the exciting prospect that amnion cells could be developed as an autologous or allogeneic therapy for preterm lung disease. I also tried to provide some insights into the likely mechanisms whereby the amnion cells are exerting their effects. I was able to demonstrate in vivo differentiation and engraftment of human amnion cells into both type I and type II alveolar epithelial cells. However, this event was rare. Rather, I believe that it is most likely that amnion cells act via modulation of the fetal inflammatory response, as described using a fetal sheep model of intrauterine inflammation (chorioamnionitis). In that model of preterm lung injury hAECs modulated LPS-induced changes in fetal lung structure and function. In both of these studies, amnion cells decreased the host cytokine response to injury, consistent with them acting via immunomodulation. Whatever the mechanisms, these two studies are the first report amelioration of “neonatal” lung disease using amnion epithelial cells and, arguably, the first to potentially offer an effective therapy for BPD. In Section Two of the thesis, I reflect on the use of betamethasone, the mainstay of current fetal therapy for the lung. I examined its effect on fetuses with intrauterine growth restriction (IUGR), a group of babies at particularly high risk of developing BPD. In this regard, experimental animal research and clinical observational studies provide some concern that while glucocorticoids may accelerate lung maturation, overall they may be detrimental to the IUGR fetus. Specifically, it has been suggested that glucocorticoids may unravel the fetal cardiovascular adaptations to placental insufficiency. Using novel fetal echocardiographic indices and fetoplacental Doppler ultrasound, I serially examined cardiac function in IUGR and appropriately grown control fetuses before and after betamethasone administration. These measurements revealed both systolic and diastolic cardiac dysfunction in IUGR fetuses compared to controls, which transiently normalized 24 hours after betamethasone administration. This was most markedly seen in left diastolic function. It remains unclear whether these changes represent improved cardiac function or loss of adaptive cardiovascular responses to progressive hypoxia. I concluded in my final study that changes from betamethasone administration to the umbilical artery Doppler waveform do not predict childhood neurodevelopmental outcome at age two. This information is relevant to infants with both BPD and IUGR, whom are at increased risk of neurodevelopmental disability. Nevertheless, despite not confirming my hypothesis this study does not answer whether developmental outcomes would be improved if management decisions had been undertaken based on this effect on umbilical artery Doppler. Prospective randomised trials are now required. In conclusion, this thesis of novel fetal therapy for the lung, from bench to bedside, offers hope for infants and families confronted with chronic lung disease. The key message articulated in my thesis is the importance of developing robust translational research and researchers if we are to provide a bright future for miracle very preterm babies.