Penn Engineers have achieved a significant milestone that could potentially close a major health equity gap for pregnant individuals dealing with preeclampsia. This condition, which emerges due to insufficient blood flow to the placenta, leads to dangerously high maternal blood pressure and restricted blood supply to the fetus.
Preeclampsia is one of the leading global culprits behind stillbirths and premature deliveries, affecting 3 to 5% of all pregnancies. Pregnant women diagnosed with preeclampsia early on in their pregnancy face a host of elevated risks for both themselves and their unborn babies. These risks span from severe health complications to the worst-case scenario of death. In the absence of a definitive cure, the current treatment options merely scratch the surface by addressing the symptoms. This includes taking medications to control blood pressure, being confined to bed rest, or making the difficult decision to deliver the baby prematurely, regardless of its viability. Deciding on a treatment path for preeclampsia can be an agonizing moral quandary for pregnant women who are already juggling numerous personal health decisions with long-term consequences.
For Kelsey Swingle, a dedicated doctoral student in the laboratory of Michael Mitchell, an Associate Professor in Bioengineering, these conventional treatment options simply do not suffice. Swingle perceives the existing gap in women’s healthcare as a potential threat to society at large. The unresolved and complex nature of preeclampsia and other similar conditions that pregnant women face, she believes, are long-overdue medical research challenges that cry out for practical, engineered solutions.
In her previous research endeavors, Swingle carried out a successful proof-of-concept study. She delved into a library of lipid nanoparticles (LNPs), the same molecular carriers that were instrumental in transporting the mRNA of the COVID vaccine into cells. Her focus was on assessing their ability to reach the placenta in pregnant mice. In her latest study, which was published in the prestigious journal Nature, Swingle expanded her investigation to 98 different LNPs. She meticulously examined their capacity to target the placenta, reduce high blood pressure, and enhance vasodilation in preeclamptic pregnant mice. Her research findings were remarkable, revealing that the most effective LNP was capable of facilitating over 100-fold greater mRNA delivery to the placenta in pregnant mice compared to an FDA-approved LNP formulation.
The results were nothing short of impressive. “Our LNP was able to deliver an mRNA therapeutic that managed to keep maternal blood pressure in check until the end of gestation and simultaneously improved fetal health and blood circulation within the placenta,” Swingle reported. “Moreover, at the time of birth, we observed an increase in the litter weight of the pups, which is a strong indication of both a healthy mother and healthy babies. I am extremely enthusiastic about the current state of this work as it holds the promise of a real treatment option for preeclampsia in human patients in the not-too-distant future.”
While the research team is on the cusp of further developing this potential cure for preeclampsia and bringing it to the human market, Swingle had to build from the ground up to make this achievement possible. She first had to establish the groundwork for conducting experiments using pregnant mice, a task that involved determining how to induce preeclampsia in this animal model. These processes are not as well-researched as one might expect. However, through her painstaking efforts in laying this foundation, Swingle’s work has not only uncovered a potential pathway for curing preeclampsia but has also opened up new avenues for research into LNP-mRNA therapeutics for other reproductive health issues.
In this particular study, preeclampsia was artificially induced in pregnant mice. Subsequently, after a comprehensive screening and analysis of their 98 LNP library to identify the most promising candidate for delivering mRNA to the placenta, the team zeroed in on one LNP. They then administered a single injection of the minimum effective dose to the preeclamptic mice on day 11 of their 20-day gestation. This one-time injection proved sufficient to treat the preeclamptic mice until the end of pregnancy. Nevertheless, the team now faces the crucial task of exploring how many doses would be required to effectively treat the condition in larger animals and, ultimately, in humans.
“At this stage of our research, our next step is to test this LNP in larger animals such as rats and guinea pigs. This will help us determine how well it performs in the ‘gold standard’ models of preeclampsia before we can even consider advancing this work to human trials,” Swingle explained. “Testing on guinea pigs is particularly fascinating as their placenta closely resembles that of a human, and their gestational period is longer, up to 72 days. We will be seeking answers to questions like ‘How many doses do these animals need?’ ‘Will the minimum effective dose change?’ and ‘How effectively does our current LNP work in each?'”
As Swingle looks ahead to the next phase of her research, she will also be collaborating in ongoing graduate research projects within the Mitchell lab. These projects are centered around further optimizing the LNP to enhance its efficiency in delivering mRNA and understanding the underlying mechanisms by which it reaches the placenta. This remains a mystery that has yet to be fully unraveled.
“We are already engaged in discussions about establishing a spin-off company with the aim of taking this LNP-mRNA therapeutic through clinical trials and eventually to the market,” she said. “However, it’s important to note that there will always be more research required to refine the drug and gain a complete understanding of how it functions.”
Swingle, who is currently in the final stages of completing her Ph.D. research, has not only spearheaded this innovative series of studies that have advanced preeclampsia treatment at Penn but has also served as an inspiration for other early-career researchers in the field of women’s health.
“Over the past few years, Kelsey has been actively involved in growing and leading a team of engineers in my lab who are deeply passionate about women’s health,” Mitchell said. “She truly grasps the significance of a robust and collaborative scientific community in driving cutting-edge research, and I have no doubt that she will continue to make significant contributions as she helps bring women’s health into the spotlight.”
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