Transamniotic Delivery of Surfactant Protein B mRNA in a Healthy Model.

Abstract

INTRODUCTION We sought to determine whether exogenous surfactant protein B (SPB) mRNA could be incorporated and translated by the fetal lung after simple transamniotic administration. METHODS Fetuses (n=149) of twelve time-dated dams underwent intra-amniotic injections of either human SPB (hSPB) mRNA encapsulated into lipopolyplex (mRNA, n=99), or of lipopolyplex without mRNA (control; n=50) on gestational day 17 (E17, term=E21-22). Lungs were screened for hSPB by ELISA daily until term. Phosphatidylcholine (a surrogate for surfactant production) was measured in the amniotic fluid by fluorometric assay. Statistical analysis included nonparametric Wilcoxon rank sum test. RESULTS Significantly improved survival in the mRNA group compared to controls was observed at E18 (100% vs. 85.7%) and E20 (100% vs. 83.3%) (both p<0.001). When controlled by mRNA-free injections, hSPB protein was detected in the mRNA group's lungs at E18, 19, and term (p=0.002 to <0.001). Amniotic fluid phosphatidylcholine levels were increased compared to control at term [285.9 (251.1, 363.9)μM vs. 263.1 (222.8, 309.1)μM], however this did not reach significance (p=0.33). CONCLUSIONS Encapsulated exogenous SPB mRNA can be incorporated and translated by fetal lung cells following intra-amniotic injection in a healthy rat model. Transamniotic mRNA delivery could become a novel strategy for perinatal surfactant protein replacement.