A lipid nanoparticle delivers mRNA cure for pre-eclampsia
The 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.
In previous research, the researchers 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 the latest study, published in Nature, the authors 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. The 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 the author. “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, the authors had to start from scratch to make this work possible. They 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, the 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 the author. “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. We 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 the author. “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?’”
