Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 32, Issue -, Pages 594-602Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2023.04.018
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Using a rat model of CDH, this study investigated the expression of miR200b and the TGF-beta pathway at different gestational times. The results showed that delivering miR200b-loaded nanoparticles to fetal rats with CDH via vitelline vein injection resulted in changes in the TGF-b pathway, leading to improved lung size, morphology, and pulmonary vascular remodeling. This is the first demonstration of in utero epigenetic therapy to improve lung growth and development.
Structural fetal diseases, such as congenital diaphragmatic hernia (CDH) can be diagnosed prenatally. Neonates with CDH are healthy in utero as gas exchange is managed by the placenta, but impaired lung function results in critical illness from the time a baby takes its first breath. MicroRNA (miR) 200b and its downstream targets in the TGF-beta pathway are critically involved in lung branching morphogenesis. Here, we characterize the expression of miR200b and the TGF-beta pathway at different gestational times using a rat model of CDH. Fetal rats with CDH are deficient in miR200b at gestational day 18. We demonstrate that novel polymeric nanoparticles loaded with miR200b, delivered in utero via vitelline vein injection to fetal rats with CDH results in changes in the TGF-b pathway as measured by qRT-PCR; these epigenetic changes improve lung size and lung morphology, and lead to favorable pulmonary vascular remodeling on histology. This is the first demonstration of in utero epigenetic therapy to improve lung growth and development in a pre-clinical model. With refinement, this technique could be applied to fetal cases of CDH or other forms of impaired lung development in a minimally invasive fashion.
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