Hematogenous Routing of Exogenous Messenger RNA Delivered Into the Amniotic Fluid.

Autor: Moskowitzova K; Department of Surgery, Boston Children's Hospital/ Harvard Medical School, Boston, Massachusetts., Whitlock AE; Department of Surgery, Boston Children's Hospital/ Harvard Medical School, Boston, Massachusetts., Zurakowski D; Department of Surgery, Boston Children's Hospital/ Harvard Medical School, Boston, Massachusetts., Fauza DO; Department of Surgery, Boston Children's Hospital/ Harvard Medical School, Boston, Massachusetts. Electronic address: dario.fauza@childrens.harvard.edu.
Jazyk: angličtina
Zdroj: The Journal of surgical research [J Surg Res] 2023 Sep; Vol. 289, pp. 116-120. Date of Electronic Publication: 2023 Apr 25.
DOI: 10.1016/j.jss.2023.03.037
Abstrakt: Introduction: Therapies based on exogenous messenger RNA (mRNA) administration have emerged as a powerful novel strategy for the actual or potential treatment of an assortment of diseases, including congenital surgical pathologies. We sought to determine whether the minimally invasive transamniotic route could be an alternative for prenatal mRNA delivery.
Methods: Pregnant Sprague-Dawley dams underwent laparotomy followed by volume-matched intra-amniotic injections in all their fetuses (n = 120) of either a suspension of a custom firefly luciferase mRNA encapsulated by a lipid- and synthetic cationic polymer-based composite, or of a suspension of the same encapsulation components without mRNA, on gestational day 17 (E17; term = E21-22). On E18, E19, E20, and E21, samples from 14 fetal anatomical sites and maternal serum were procured for the screening of mRNA incorporation by host cells by measurement of luciferase activity via microplate luminometry. Statistical analysis was by Mann-Whitney U-test, including Bonferroni-adjustment.
Results: Overall survival was 87.5% (105/120). Controlled by the encapsulating composite without mRNA, luciferase activity was detected in the animals that received encapsulated mRNA in the following fetal annexes: amniotic fluid, amnion, chorion, umbilical cord, and placenta (P = 0.033 to <0.001), as well as in the following fetal sites: liver, stomach, intestines, and lungs (P = 0.043-0.002).
Conclusions: Packaged exogenous mRNA can be incorporated by the fetus at least at select anatomical sites after simple intra-amniotic administration in a rodent model. The pattern and chronology of mRNA incorporation are compatible with transplacental hematogenous routing, as well as with fetal swallowing/aspiration. Further study of transamniotic mRNA administration is warranted.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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