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Scientists discover a promising new way to reduce the risk of preterm birth

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A team of scientists has created bioengineered exosomes – microscopic extracellular vesicles – carrying an NF-κB inhibitor, and then tested their effectiveness in mice. 

This method of drug delivery helped slow the migration of fetal immune cells, reduce the risk of inflammation, and eventually avoid preterm birth.

Premature births – that occur before 37 completed weeks of pregnancy – are experienced by about 15 million women each year. According to estimates by the World Health Organization, about a million premature babies subsequently die due to complications. 

And many of those who manage to survive become disabled, have vision and hearing problems, or have learning difficulties. To avoid premature birth, it is often necessary to have continuous observation by an obstetrician and measurement of the fetus, the absence of addictions in the expectant mother – such as smoking, alcohol or drug use, and sometimes antenatal steroid injections.

Pregnancy is balanced by the endocrine, hormonal and immune systems. Disruption of the balanced activity of various intrauterine tissues of the fetus and maternal-fetal prepares them for the changes associated with childbirth. Intrauterine inflammation resulting from disturbed uterine homeostasis is one of the biological effectors of childbirth: it is characterized by infiltration and activation of immune cells both in the tissues of the fetus and in the tissues of the uterus of a pregnant woman, as well as increased levels of pro-inflammatory cytokines and chemokines mediated by the pro-inflammatory transcription factor NF-κB and reduced level of anti-inflammatory cytokines and chemokines.

Inflammation is accelerated by endocrine and paracrine mediators after fetal maturation is complete. Premature disruption of immune homeostasis and inflammation due to infection or other risk factors leads to premature birth. Most of them are associated with intrauterine infections that overcome the immune tolerance, causing an inflammatory response: the fact is that the cells of the fetus, including the patient, can penetrate into the mother’s tissues during pregnancy. And a new study by University of Texas physicians published in Science Advances confirms this.

The authors examined several important assumptions about the relationship between the health of a mother and her unborn child. A better understanding of the contribution of fetal immune cells to the birth process will help develop rational therapies to minimize inflammation and reduce the incidence of preterm labor, they said.

First, it was necessary to prove that fetal cells, in particular immune cells, actually migrated through the mother’s body to the tissues of her uterus, potentially causing inflammation that accelerates labor. To do this, female mice were crossed with genetically modified males – they were injected with a red fluorescent dye: thanks to it, after mating, the cells of the developing fetus also turned red, so that their migration through the mother’s body could be easily tracked. In addition, scientists have developed a model that allowed the identification of fetal immune cells reaching maternal tissues.

Then, using exosomes – microscopic extracellular vesicles ranging in diameter from 30 to 100 nanometers, which tissue and organ cells secrete into the intercellular space – to load protein through optically reversible protein-protein interactions, American researchers, in collaboration with the South Korean company ILIAS Biologics, Inc., created exosomes, which contain an anti-inflammatory drug, an NF-κB inhibitor called an IκB super-repressor (SR). The next step was to find out if exosomes are able to deliver the NF-kB inhibitor from the mother’s bloodstream to the fetus.

“Exosomes are natural nanoparticles or vesicles, trillions of them are constantly circulating in our body. By packaging the drug inside a bioengineered exosome and injecting it intravenously into the mother, they travel through the circulatory system, cross the placental barrier and enter the fetus, delivering the drug,” said Dr. Ramkumar Menon, one of the authors of the work.

As it turned out, exosomes were indeed able to effectively deliver the drug to the fetus (they were injected on the 15th day of pregnancy), thereby not only slowing down the migration of its immune cells and increasing vitality, but at the same time reducing the risk of inflammation, reducing interleukin-6 levels and interleukin-10 in maternal plasma and, as a result, transferring labor in female mice 24 hours later (the total pregnancy in these rodents lasts 17-24 days). Of course, further research is needed to confirm laboratory results, including human clinical trials.

“The rate of preterm birth has not declined over the past several decades, and our technology – bioengineered exosomes – may pave the way for other drug delivery methods to treat the underlying cause of inflammation in the fetus,” Menon said. 

In addition, the new method can be used to treat other adverse pregnancy complications.

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