Transamniotic Fetal Delivery of Cystic Fibrosis ( CF ) Transmembrane Conductance Regulator ( CFTR ) mRNA

ABSTRACT We sought to determine whether a cystic fibrosis transmembrane conductance regulator (CFTR) mRNA could be administered to the fetus via the transamniotic route as a potential strategy for the perinatal management of cystic fibrosis‐associated meconium ileus. Nine pregnant Sprague Dawley dams underwent volume‐matched intra‐amniotic injections in all their fetuses ( n = 109) of either a suspension of a human CFTR mRNA encapsulated by a semi‐synthetic composite, lipopolyplex (mRNA group; n = 98), or of a suspension of the same composite free of mRNA (control group; n = 11), on gestational day 17 (E17; term = E21). At daily time points until term, fetal small bowel and lungs, along with maternal serum, were quantitatively screened for the human CFTR protein by ELISA. Statistical analysis was by the nonparametric Wilcoxon rank sum test with Bonferroni adjustment. Overall fetal survival was 85.3% (93/109), with no significant differences between the groups or time points. When controlled by mRNA‐free injections, human CFTR was detected in the small bowel from the mRNA group at all time points ( p < 0.001 for all), increasing initially over time. Human CFTR was detected comparably in the lungs from both groups, suggesting interspecies homology at that anatomical site. No human CFTR was detected in maternal serum. Encapsulated exogenous mRNA encoding for the cystic fibrosis transmembrane conductance regulator protein can be incorporated and translated by fetal small bowel cells after simple intra‐amniotic injection in a healthy rodent model. Transamniotic mRNA delivery could become a novel strategy for the perinatal management of meconium ileus associated with cystic fibrosis.