There’s no shortage of applications for RNA technology, from vaccines to treating wrinkles. Now, researchers from the University of Pennsylvania are looking to add another indication to the list: preeclampsia, a common but dangerous condition in pregnancy where malformed blood vessels to the placenta prevent proper blood flow between the mother and the fetus, jeopardizing the health of both.
In a paper published Feb. 15 in the Journal of the American Chemical Society, the team described how it developed and used lipid nanoparticles, or LNPs, to deliver mRNA expressing a blood vessel-expanding protein to the placentas of mice. “As we continue to work towards translating these LNPs from bench top to animal models to perhaps patients one day, this therapy has the potential to benefit both maternal and fetal health,” lead author Kelsey Swingle, a Ph.D. student in the lab of Michael Mitchell, Ph.D., told Fierce Biotech Research in an email.
Despite having been characterized for at least 100 years, scientists still don’t know exactly what causes preeclampsia. Theories range from poor placental blood vessel formation to the impact of hormones, mineral deficiencies or inflammation. Patients present with high blood pressure accompanied by some combination of kidney impairment, fluid in the lungs, low platelets or headaches, and they leave their doctors’ offices with prescriptions for lifestyle adjustments and blood pressure drugs. The babies of mothers with preeclampsia are often born prematurely—which comes with its own complications.
The key to resolving preeclampsia is reinstating normal blood flow to the placenta by dilating the blood vessels. The most successful strategy researchers have attempted so far is either overexpressing the protein vascular endothelial factor, or VEGF, or down-regulating its receptor sFlt-1. Some research teams have delivered adenovirus vectors encoding for VEGF to the uterine arteries, while others have tried subcutaneous injections of small interfering RNA bound with cholesterol so it disrupts production of sFLT-1.
The new study from Swingle and her team marks the first time scientists have successfully delivered mRNA to the placenta using an LNP. LNPs are tiny clusters of ionizable fats. They’re used to deliver therapeutic mRNA—most famously in the case of the COVID-19 vaccines—as well as gene therapies, small-molecule drugs, immunotherapies and more.
Where in the body LNPs can drop off their payload depends on their structure. Without a precedent for placenta-bound LNPs to draw from, Swingle’s team decided designed their particles based on ones they had used in previous research on drug delivery to the liver. The liver and the placenta have some important similarities, the researchers noted. Both are highly vascularized with high blood flow.
With this in mind, the scientists designed a library of 15 LNPs, each using a different ionizable lipid. They then added them to placental trophoblasts, a type of cell that’s found in the placenta of both mice and humans, and tested how well they delivered mRNA for a glowing protein called luciferase into the cells. After coming up with a shortlist of three LNPs to test further, they moved on to mice, this time injecting the LNPs into their tail veins. One of the LNPs, dubbed A4, stood out. It tracked to the placenta and delivered its mRNA with higher efficiency than the others, without any of the payload finding its way into the fetus.
Next, the scientists moved to testing A4 with VEGF mRNA in pregnant mice. They found that it was successfully able to deliver the mRNA to the placenta, with no signs of toxicity and only minimal, transient inflammation—a point of concern, as additional inflammation would compound the already inflamed placenta in preeclampsia.
Finally, they assessed whether the VEGF mRNA was indeed capable of dilating the placenta blood vessels. Working again in pregnant mice, they injected the VEGF mRNA into their tail veins, then analyzed their placentas 48 hours later. They found that the mRNA was able to dilate the blood vessels successfully, acting on not only the trophoblasts but also endothelial cells and immune cells within the placenta.
The results laid the groundwork for testing the therapy in mice with preeclampsia, work that’s already underway, according to Swingle. The lab hopes that it will eventually wind up in human patients, so expecting parents with preeclampsia don’t have to choose between their own health and the health of their baby.
“When a patient has preeclampsia, they might be presented with the impossible question of whether they should deliver their baby early to resolve their own high blood pressure or carry their baby closer to term to give them time to more fully develop,” Swingle said. “This therapy, by helping to improve blood flow from the mother to the fetus through the placenta, has the potential to address both the mom’s high blood pressure and the health risks for the baby that are associated with preterm birth.”