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Transamniotic Delivery of Surfactant Protein B (SPB) mRNA: a Potential Novel Strategy for the Perinatal Management of Congenital SPB Deficiencies and Surfactant Replacement Therapy
Kamila Moskowitzova, MD; Abbie E Naus, MD; Tanya T Dang; David Zurakowski, PhD; Dario O Fauza, MD, PhD Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA

Background: Congenital surfactant protein B (SPB) deficiency is associated with very high mortality due to respiratory insufficiency, especially in premature infants. We investigated whether exogenous SPB mRNA could be incorporated and translated by the fetal lung after transamniotic administration.

Methods: Twelve time-dated pregnant Sprague Dawley dams underwent laparotomy followed by volume-matched intra-amniotic injections in all fetuses (n=149) 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). Fetal lung and amniotic fluid samples were procured daily thereafter until term. Lungs were screened for hSPB production by ELISA. Phosphatidylcholine (a surrogate for overall pulmonary surfactant production) levels were measured in the amniotic fluid by fluorometric assay. Statistical analysis was by nonparametric Wilcoxon rank sum test and generalized estimated equations regression.

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, Figure A). Amniotic fluid phosphatidylcholine levels were increased compared to control at term (31930.2 vs. 28129.3 ng/mL; Figure B), however it did not reach significance in this series (p=0.33).

Conclusion: Encapsulated exogenous mRNA encoding for surfactant protein B can be incorporated and translated by fetal lung cells following simple intra-amniotic injection in a healthy rat model. Transamniotic mRNA delivery could become a novel strategy for perinatal surfactant protein replacement.
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