Penn Engineers have made a critical breakthrough that bridges a major healthy equity gap for pregnant people with pre-eclampsia, a condition that arises due to insufficient blood flow to the placenta and results in high maternal blood pressure and restricted blood flow to the fetus.
Pre-eclampsia is one of the leading causes of stillbirths and prematurity worldwide, and it occurs in 3 to 5% of pregnancies. Pregnant people diagnosed with pre-eclampsia early in pregnancy face higher risks for themselves and their babies, including severe health issues and death. Without a cure, options for these patients only treat symptoms, such as taking blood pressure medication, being on bed rest or delivering prematurely regardless of the viability of their baby. Making a decision to treat pre-eclampsia in any manner can be a moral conundrum for pregnant people already confronting many personal health decisions with long-standing impacts.
For Kelsey Swingle, a doctoral student in the lab of Michael Mitchell , Associate Professor in Bioengineering, these options are not enough. Swingle sees the gap in women's health care as a risk to society, and the uncured and complex conditions that pregnant people face as medical research challenges that are long overdue for real, engineered solutions.
In previous research, Swingle conducted a successful proof-of-concept study that examined a library of lipid nanoparticles (LNPs), the delivery molecules that helped get the mRNA of the COVID vaccine into cells, and their ability to reach the placenta in pregnant mice. In her latest study , published in Nature, Swingle examined 98 different LNPs and their ability to get to the placenta and decrease high blood pressure and increase vasodilation in pre-eclamptic pregnant mice. Her work shows that the best LNP for the job was one that mediates more than 100-fold greater mRNA delivery to the placenta in pregnant mice than an FDA-approved LNP formulation.
The drug worked. "Our LNP was able to deliver an mRNA therapeutic that reduced maternal blood pressure through the end of gestation and improved fetal health and blood circulation in the placenta," says Swingle. "Additionally, at birth we saw an increase in litter weight of the pups, which indicates a healthy mom and healthy 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 further developing this cure for pre-eclampsia and getting it to the market for human use is on the horizon for the research team, Swingle had to start from scratch to make this work possible. She first had to lay the groundwork to run experiments using pregnant mice and determine how to induce pre-eclampsia in this animal model, processes that are not as well studied. But, by laying this groundwork, Swingle's work has not only identified an avenue for curing pre-eclampsia, it also opens doors for research on LNP-mRNA therapeutics addressing other reproductive health challenges.
"It turns out that there are relatively few studies that have been done with mRNA LNPs in pregnant mice, and little to none done in pre-eclamptic mice," says Swingle. "Everything is different in pregnancy research. In mice, instead of tracking gestational weeks, we track gestational days so we know exactly how far along 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 imitates the disease in humans."
In this study, pre-eclampsia was induced in pregnant mice. Then, after the team screened and analyzed their 98 LNP library to determine which would be the best at delivering mRNA to the placenta, they took one LNP forward, injecting the pre-eclamptic mice with the minimum effective dose once at day 11 of their 20-day gestation. This one-time injection cured pre-eclamptic mice until the end of pregnancy, but now the team must explore how many doses would be needed to treat the condition in larger animals and humans.
"At this stage in our research, we would bring this LNP to larger animals such as rats and guinea pigs first to determine how well it works in the 'gold standard' models of pre-eclampsia before we could advance this work to human trials," says Swingle. "Testing our LNP on guinea pigs will be particularly interesting, as their placenta closely resembles a human's and their gestational period is longer, up to 72 days. We will be asking the questions 'How many doses do these animals need?' 'Will the minimum effective dose change?' and 'How well does our current LNP work in each?'"
As Swingle thinks ahead for next steps in her research, she will also collaborate in ongoing graduate research projects in the Mitchell lab focusing on further optimizing the LNP to deliver the mRNA even more efficiently, as well as understanding the mechanisms of how it gets to the placenta, a question still not fully answered.
"We are already in talks about creating a spin-off company and want to work on bringing this LNP-mRNA therapeutic to clinical trials and the market," she says. "But, there will always be more research to do to improve the drug and to truly understand how it works."
Swingle, who is currently finishing up her Ph.D. research, has not only successfully led this new series of studies advancing pre-eclampsia treatment at Penn, she has also inspired other early career researchers in the field of women's health.
"Over the last few years, Kelsey has enthusiastically helped grow and lead a team of engineers in my lab who are passionate about women's health," says Mitchell. "She truly understands the importance of a strong and supportive scientific community to execute cutting-edge research, and I'm confident she will continue to thrive as she helps bring women's health into the spotlight."
This work is funded by the National Institutes of Health (DP2 TR002776, NICHD R01 HD115877), the National Science Foundation (CBET-2145491, 1845298), and a Burroughs Wellcome Fund Career Award at the Scientific Interface.
