Combined transamniotic delivery of surfactant proteins B and C mRNA enhances preterm fetal surfactant production in a rodent model.

Abstract

Prematurity remains the leading cause of neonatal mortality and morbidity, largely due to pulmonary surfactant deficiency. We compared isolated and combined transamniotic delivery of surfactant proteins B (SPB) and C (SPC) mRNA. Fetuses (n = 415) from thirty-two time-dated dams underwent intra-amniotic injections on gestational day 17 (E17, term= E21-22) of lipopolyplex-encapsulated mRNA consisting of either human SPB (hSPB) mRNA (n = 151), human SPC (hSPC) mRNA (n = 102), a combination of hSPB+hSPC mRNA (n = 113), or lipopolyplex without mRNA (n = 49). Fetal lungs were screened for hSPB and hSPC by ELISA daily until term. Phosphatidylcholine was measured in the amniotic fluid. Controlled by mRNA-free injections, the hSPB protein was detected in the SPB mRNA group only at E18 and E19, whereas in the SPB + SPC mRNA group it was detected at every preterm timepoint (E18-E20), either separately or combined (p < 0.001 for all). The hSPC protein was detected in the SPC mRNA group only at E18 (p = 0.015). Amniotic fluid phosphatidylcholine was significantly increased in the SPC mRNA and SPB + SPC mRNA groups compared to controls (p < 0.001). Combined transamniotic delivery of exogenous mRNA encoding for SPB and SPC enhances surfactant production prior to term when compared with isolated mRNA administrations in a healthy rat model. Transamniotic mRNA delivery may become a novel strategy for surfactant replacement therapy. Combined transamniotic mRNA delivery for surfactant proteins B and C enhances preterm surfactant production. Transamniotic mRNA delivery can be achieved in a short time frame, for example compatible with select clinical settings of preterm labor.