Grant: Canada Postdoctoral Research Award (CPRA) program

Congenital diaphragmatic hernia (CDH) is a serious condition occurring in babies before birth that leads to severely underdeveloped lungs. More than half of affected newborns do not survive because their lungs are too small to support breathing. Research has shown that a natural genetic molecule called miR-200b is often low in CDH lungs and restoring it can improve lung growth. However, miR-200b breaks down quickly in the body and must be packaged for safe delivery. We want to develop tiny protective packages called lipid nanoparticles (LNPs) that can deliver miR-200b. Two delivery approaches will be considered: injection into the amniotic fluid so the baby swallows or inhales the treatment, or injection into the maternal bloodstream so the therapy crosses the placenta and enters the baby. Building on past research, we will design miR-200b-loaded LNPs that specifically target the fetal lungs for amniotic injection. For maternal injection, we will attach antibodies that naturally cross the placenta to help the miR-200b treatment reach the lungs. To test these therapies, we will use "organ-on-a-chip" technology, which recreates miniature models of fetal lungs and the placenta in the lab. We will mimic underdeveloped lungs in the models using substances that interfere with lung growth. The miR-200b-loaded LNPs will be added either directly to the lung models (amniotic route) or through placenta chips connected to the lung models (maternal route). By observing the response of the underdeveloped lung models after treatment, we can measure how well the treatments work and how safe they are, without relying only on animal testing. A successful therapy could improve lung development in babies before they are born, reduce the healthcare challenges associated with CDH, and improve life for infants with this condition globally.