Engineers at the University of Pennsylvania have made a crucial breakthrough that promises better outcomes for pregnancies at risk of preeclampsia, a condition that occurs due to insufficient blood flow to the placenta, leading to maternal high blood pressure and restricted blood flow to the fetus.
Pre-eclampsia is a leading cause of stillbirth and prematurity worldwide, and occurs in 3-5% of pregnancies. Without a cure, the options available to these patients only treat the symptoms, such as taking blood pressure medications, bed rest, or premature delivery, regardless of the viability of their baby.
Making the decision to treat pre-eclampsia in any way can be a moral conundrum, balancing many personal health decisions with long-term impacts – and for Kelsey Swingle, a doctoral student in the Bioengineering Lab from UPenn, these options are not enough.
In previous research, she successfully conducted a proof-of-concept study that looked at a library of lipid nanoparticles (LNPs) – which are the delivery molecules that helped deliver COVID vaccine mRNA into cells – and their ability to reach the placenta in the cells. pregnant mice.
In his latest studypublished in Nature, Swingle examined 98 different LNPs and their ability to reach the placenta, decrease high blood pressure, and increase vasodilation in pre-eclamptic pregnant mice.
His work shows that the best LNP for this task was one that resulted in more than 100 times greater mRNA delivery to the placenta in pregnant mice than an FDA-approved formulation of LNP.
The medicine worked.
“Our LNP was able to provide an mRNA-based treatment that reduced maternal blood pressure until late gestation and improved fetal health and blood flow in the placenta,” said Swingle..
“Additionally, at birth, we saw an increase in the litter weight of the puppies, which indicates a healthy mother and babies. I am very excited about this work and its current stage because it could offer a real treatment for pre-eclampsia in human patients in the very near future.
While the research team plans to further develop this pre-eclampsia remedy and commercialize it for human use, Swingle had to start from scratch to make this work possible. She first had to lay the groundwork to conduct experiments on pregnant mice and determine how to induce pre-eclampsia in this animal model, processes that are less well studied.
But, by laying this foundation, Swingle’s work has not only identified a pathway to cure pre-eclampsia, but it also opens the doors to research into LNP-mRNA therapies addressing other reproductive health concerns.
“It turns out that there are relatively few studies that have been done with mRNA LNPs in pregnant mice, and few if any studies done in preeclamptic mice,” says Swingle. “Everything is different in pregnancy research. In mice, instead of tracking weeks of gestation, we track days of gestation so we know exactly where their pregnancy is. I had to learn the anatomy of a mouse placenta and then determine the best ways to establish a mouse model of pre-eclampsia that best mimics the disease in humans.
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In this study, pre-eclampsia was induced in pregnant mice. Then, they injected LNP with the minimum effective dose once, on day 11 of their 20-day gestation. This single injection cured pre-eclamptic mice through the end of pregnancy, but the team now needs to explore how many doses would be needed to treat the disease in larger animals and in humans.
“At this stage of our research, we would first apply this LNP to larger animals, such as rats and guinea pigs, to determine its effectiveness in ‘gold standard’ models of pre-eclampsia, before being able to advance “this work toward human trials,” Swingle said.
“Testing our LNP on guinea pigs will be particularly interesting, because their placenta is very similar to that of humans and their gestation period is longer, up to 72 days. We will ask the questions “How many doses do these animals need?” » “Will the minimum effective dose change? and “How well is our current LNP working in each?” »
As Swingle considers the next steps in her research, funded by the National Institutes of Health and the National Science Foundation, she will also collaborate to further optimize LNP to deliver mRNA even more efficiently, as well as to understand the mechanisms of how it reaches the placenta, a question that has not yet been fully resolved.
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They are already in talks about creating a spinoff company and want to work on bringing this LNP-mRNA treatment to clinical trials and the market.
Swingle, who is currently completing his Ph.D. research, has not only successfully led this new series of studies advancing the treatment of pre-eclampsia at Penn, but she has also inspired other early career researchers in the field as she continues to flourish all by putting women’s health in the spotlight.
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