In utero delivery of miRNA induces epigenetic alterations and corrects pulmonary pathology in congenital diaphragmatic hernia

Abstract

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. During fetal development, lungs are capable of remarkable growth and the fetus does not yet require lung function for gas exchange. MicroRNA (miR) 200b and its downstream targets in the TGF{beta} pathway are critically involved 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 NPs loaded with miR200b given systemically to fetal rats result in changes in the TGF{beta} pathway; these epigenetic changes improve lung size, lung morphology, and lung vascularization. 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. eTOC SynopsisIn utero treatment with NPs loaded with miR200b improves lung development in a rat model of CDH. miR200b treatment epigenetic changes in the TGF{beta}, leads to larger lungs with more airspace and favorable pulmonary vascular remodeling. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/482144v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@3531caorg.highwire.dtl.DTLVardef@57ff5aorg.highwire.dtl.DTLVardef@13d6ee9org.highwire.dtl.DTLVardef@3cb3d8_HPS_FORMAT_FIGEXP M_FIG C_FIG