Penn Engineers have achieved a remarkable milestone that could potentially close a significant health equity gap for pregnant individuals suffering from preeclampsia. This condition, which stems from inadequate blood flow to the placenta, leads to elevated maternal blood pressure and restricted blood supply to the fetus.
Preeclampsia is among the top global causes of stillbirths and premature births, affecting 3 to 5% of pregnancies. Those diagnosed with preeclampsia early in pregnancy face heightened risks for both themselves and their babies, including severe health complications and even death. Since there is currently no cure, the available options merely address the symptoms. These include taking blood pressure medications, bed rest, or resorting to premature delivery regardless of the fetus’s viability. Deciding on a treatment approach for preeclampsia can present a moral dilemma for pregnant individuals who are already grappling with numerous personal health decisions with far-reaching consequences.
For Kelsey Swingle, a doctoral student in the lab of Michael Mitchell, an Associate Professor in Bioengineering, these existing options are insufficient. Swingle views the gap in women’s healthcare as a threat to society and the unresolved and complex conditions faced by pregnant individuals as overdue medical research challenges that demand engineered solutions.
In prior research, Swingle carried out a successful proof-of-concept study. She examined a library of lipid nanoparticles (LNPs), the same delivery molecules used to transport the mRNA of the COVID vaccine into cells, and evaluated their ability to reach the placenta in pregnant mice. In her latest study, published in Nature, Swingle investigated 98 different LNPs and their efficacy in reaching the placenta, reducing high blood pressure, and increasing vasodilation in preeclamptic pregnant mice. Her findings revealed that the most effective LNP was capable of mediating over 100-fold greater mRNA delivery to the placenta in pregnant mice compared to an FDA-approved LNP formulation.
The drug proved successful. “Our LNP was able to deliver an mRNA therapeutic that maintained reduced maternal blood pressure until the end of gestation and enhanced fetal health and blood circulation in the placenta,” Swingle stated. “Furthermore, at birth, we observed an increase in the litter weight of the pups, suggesting both a healthy mother and healthy babies. I am extremely excited about this work and its current progress as it could potentially provide a genuine treatment for preeclampsia in human patients in the near future.”
Although further development of this cure for preeclampsia and its introduction to the human market are on the research team’s agenda, Swingle had to commence from the ground up to make this possible. She first had to establish the foundation for conducting experiments using pregnant mice and determine how to induce preeclampsia in this animal model, areas that have not been extensively studied. However, by laying this groundwork, Swingle’s work has not only identified a path towards curing preeclampsia but has also opened doors for research on LNP-mRNA therapeutics to address other reproductive health issues.
In this study, preeclampsia was induced in pregnant mice. Subsequently, after screening and analyzing their 98 LNP library to identify the most suitable candidate for delivering mRNA to the placenta, the team selected 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 single injection effectively treated the preeclamptic mice until the end of pregnancy. Nevertheless, the team now needs to explore the number of doses required to treat the condition in larger animals and humans.
“At this stage of our research, we will initially test this LNP in larger animals such as rats and guinea pigs to assess its performance in the ‘gold standard’ models of preeclampsia before proceeding to human trials,” Swingle explained. “Testing on guinea pigs will be particularly intriguing as their placenta closely resembles that of a human, and their gestational period is longer, up to 72 days. We will be investigating questions such as ‘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 plans the next steps in her research, she will also collaborate in ongoing graduate research projects in the Mitchell lab. These projects focus on further optimizing the LNP to enhance mRNA delivery efficiency and understanding the mechanisms by which it reaches the placenta, a question that remains partially unanswered.
“We are already in discussions about establishing a spin-off company and aim to progress this LNP-mRNA therapeutic to clinical trials and the market,” she said. “However, there will always be additional research required to refine the drug and comprehensively understand its mode of action.”
wingle, who is nearing the completion of her Ph.D. research, has not only spearheaded this new series of studies advancing preeclampsia treatment at Penn but has also inspired other early-career researchers in the field of women’s health.
“Over the past few years, Kelsey has actively contributed to the growth and leadership of a team of engineers in my lab who are dedicated to women’s health,” Mitchell said. “She truly appreciates the significance of a robust and collaborative scientific community in executing cutting-edge research, and I am confident that she will continue to excel as she helps bring women’s health into the spotlight.”
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