Thursday, November 21, 2024
11/21/2024
PROJECT ABSTRACT Recently released “Born Too Soon” by WHO and many other global organizations (May 2023) reported 152 million preterm births (PTB) worldwide in the past decade, with 15 million neonatal deaths due to prematurity complications. Current interventions are insufficient to reduce the rates of PTB that involve both the fetus and the mother as patients; however, interventions are restricted to the maternal uterine tissues and do not address the fetal inflammatory response, which is one of the major triggers of labor at term and preterm. To address drug delivery to the fetus and to reduce the fetal and maternal inflammatory response, we have successfully developed and tested extracellular vesicle (EVs; exosomes) mediated delivery of anti-inflammatory cytokine interleukin-10 (eIL-10). This approach improves IL-10’s half-life in the body and avoids its intraamniotic administration for effectiveness. Our laboratory has engineered EVs by electroporation to contain the natural anti-inflammatory protein IL-10. Engineered EVs retain their normal characteristics and cargo functionally active IL-10 and show the following: (1) In vitro efficacy to reduce NF-kB activation and inflammatory cytokine production in vitro in feto-maternal cells, (2) successful transplacental delivery of eIL-10 to delay PTB by over 72 hours in LPS-induced PTB in mouse models with a reduction in histologic chorioamnionitis and fetal and maternal systemic inflammatory response, and (4) eIL-10 did not cause long term immunosuppression in the neonates or mothers. Several unanswered questions remain before advancing eIL-10 to clinical trials. We will test the hypothesis that eIL-10 is safe, stable, and specific in reducing feto-maternal inflammation to delay PTB without any prenatal or postnatal complications. We will test the hypothesis using the following aims: SA# 1: Determine PK/PD, toxicity, pregnancy, and neonatal outcomes associated with eIL-10 in pregnant mouse models. SA#2: Determine the toxicity and PK/PD in non-pregnant and pregnant nonhuman primate models. In addition, using a 3rd aim, the reproducibility of animal model data of eIL-10 will be tested. We will use a highly innovative humanized microphysiologic model of the feto-maternal interface that contains interconnected fetal membrane/placental-decidual interface organs on a chip (FM-PL-OOC). SA#3: To determine the utility of FM- PL-OOC in defining the propagation, absorption, cytotoxicity, and efficacy of eIL-10. Comparison of data with Aims 1&2 will validate our in vitro model and validate the use of microphysiologic-based devices for future preclinical trials. Our approach will enable the use of alternative approaches to animal testing to obtain regulatory agency approval for the investigation of the safety and efficacy of a drug during pregnancy. This proposal will yield data from three independent models to define the toxicity, PK, and PD of eIL-10, a novel interventional strategy to decrease inflammation-associated PTB.
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