Transamniotic Fetal Delivery of Human Alpha-1 Antitrypsin mRNA in a Healthy Rodent Model.

Alpha-1 antitrypsin deficiency (AATD) can manifest at any age, including the perinatal period. Its manifestations include obstructive lung disease, which can be severe and for which current therapies are of limited benefit. We sought to determine whether the transamniotic route could be a viable alternative for administering AAT mRNA to the fetus. Twelve pregnant dams underwent volume-matched intra-amniotic injections in all their fetuses (n = 139) of either a suspension of human AAT (hAAT) mRNA encapsulated by a synthetic cationic polymer-based composite, lipopolyplex (mRNA group; n = 99) or of lipopolyplex free of mRNA (controls; n = 40), on gestational day 17 (E17; term = E21). Fetal lung and liver samples were procured daily thereafter until term to screen for hAAT by ELISA. Liver function panels were performed at term. Statistical analysis included median regression (p < 0.05). Fetal survival was 79% (110/139), significantly higher in the mRNA group (p = 0.012). Controlled by mRNA-free injections, hAAT was found in the fetal lungs at all time points (p = 0.005 to < 0.001) but in the liver only at E20, suggesting interspecies homology manifesting at that site. The term liver function panels were comparable between groups. Encapsulated exogenous mRNA encoding for human alpha-1 antitrypsin protein can be incorporated and translated by fetal lung cells following simple intra-amniotic injection in a healthy rat model. Fetal hepatic incorporation and translation remain to be determined in a model with minimal to no human homology. Transamniotic mRNA delivery could become a novel strategy for the perinatal management of alpha-1 antitrypsin deficiency.