Engineers have created a lipid nanoparticle (LNP) designed to transport mRNA therapies to the placenta, aiming to treat pre-eclampsia in mice, with human trials on the horizon.
Researchers at Penn have achieved an important advancement that addresses a significant healthcare equity issue for pregnant individuals suffering from pre-eclampsia. This condition arises from inadequate blood flow to the placenta, leading to increased maternal blood pressure and compromised blood circulation to the fetus.
Pre-eclampsia is a major contributor to stillbirths and premature births globally, affecting 3 to 5% of pregnancies. Those diagnosed with pre-eclampsia early in their pregnancy face greater risks for themselves and their babies, which can include severe health complications and even death. Currently, there is no cure; available options focus on managing symptoms, such as taking medication to lower blood pressure, resting in bed, or delivering the baby early, regardless of its readiness for the outside world. Making decisions about treating pre-eclampsia can create moral dilemmas for those pregnant individuals already faced with numerous health decisions that have far-reaching consequences.
For Kelsey Swingle, a doctoral student working under Michael Mitchell, an Associate Professor in Bioengineering, these existing options fall short. Swingle views the shortcomings in women’s healthcare as a broader societal concern, with the unresolved and complicated conditions that expectant individuals face representing a critical challenge that requires innovative solutions.
Previously, Swingle conducted successful proof-of-concept research that evaluated various lipid nanoparticles (LNPs)—the same delivery systems used to introduce the mRNA in COVID vaccines—and their capacity to reach the placenta in pregnant mice. In her recent study, published in Nature, she analyzed 98 distinct LNPs to assess their capability to access the placenta, reduce maternal blood pressure, and enhance blood flow in pre-eclamptic pregnant mice. The findings revealed that the most effective LNP was capable of delivering mRNA to the placenta over 100 times more efficiently than an existing FDA-approved LNP.
The treatment proved successful. “Our LNP successfully delivered an mRNA therapy that lowered maternal blood pressure throughout pregnancy and improved fetal health along with blood circulation in the placenta,” Swingle explains. “Moreover, at the time of birth, we observed an increase in the weight of the pups, indicating both a healthy mother and healthy babies. I am incredibly excited about this stage of our work, as it holds the potential for actual treatment options for pre-eclampsia in future human patients.”
As the research team progresses toward commercializing this pre-eclampsia treatment for human use, Swingle initially had to develop a new experimental approach. She needed to establish protocols to test on pregnant mice and methods to induce pre-eclampsia in this animal model, a field that has not seen extensive study. However, she laid the necessary groundwork, leading to an avenue not only for addressing pre-eclampsia but also for further investigations into LNP-mRNA therapies focused on various reproductive health issues.
“Interestingly, relatively few investigations have been conducted on mRNA LNPs in pregnant mice, and almost none in pre-eclamptic mice,” Swingle states. “Pregnancy research has its own complexities; for example, instead of measuring in weeks, we track gestational days in mice to monitor the exact stage of pregnancy. I had to familiarize myself with mouse placenta anatomy and identify the optimal ways to create a mouse model of pre-eclampsia that closely resembles the human condition.”
In this particular study, pre-eclampsia was induced in the pregnant mice. After initially screening their library of 98 LNP types to find the ideal candidate for mRNA delivery to the placenta, the research team selected one LNP and injected the pre-eclamptic mice with a minimum effective dose on day 11 of their 20-day gestation period. This single injection successfully treated the pre-eclamptic condition until the end of their pregnancy, but now the team must investigate how many doses would be necessary for treatment in larger animals and in humans.
As a next step in their research, Swingle’s team plans to test this LNP in larger animals like rats and guinea pigs to evaluate its effectiveness in established models of pre-eclampsia before advancing to human trials. “Testing in guinea pigs will be particularly enlightening because their placenta closely resembles that of humans, and their gestation period lasts up to 72 days. We will need to explore questions like, ‘How many doses do these animals require?’ ‘Will the minimum effective dose vary?’ and ‘How effectively does our current LNP function in each case?'”
As she prepares for the next phase of her research, Swingle will also participate in various graduate research initiatives within the Mitchell lab. These projects aim to enhance LNP efficiency in mRNA delivery and to delve deeper into understanding how the drug reaches the placenta, a topic that remains partially unclear.
“We are already discussing the potential for a spin-off company and our goal is to transition this LNP-mRNA therapy to clinical trials and subsequently to market,” she remarks. “However, additional research will always be essential to refine the drug and fully comprehend its mechanisms.”
Swingle, nearing the completion of her Ph.D. research, has not only spearheaded this innovative research trajectory at Penn, but she has also motivated emerging researchers in the women’s health field.
“In the past few years, Kelsey has played a vital role in fostering and leading a team of engineers in my lab who are dedicated to women’s health,” Mitchell shares. “She truly appreciates the value of a robust and supportive scientific community in advancing groundbreaking research, and I’m confident she will continue to excel in bringing attention to women’s health issues.”
This research is supported 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.