Scientists have successfully shielded expectant mice from the life-threatening condition of pre-eclampsia with a solitary injection. As the shot is administered, it utilizes mRNA instructions to synthesize a protein that promptly repairs damage to the placenta, thereby safeguarding both mother and developing fetus in this critical scenario.
According to the World Health Organization, pre-eclampsia annually accounts for approximately 75,000 maternal deaths and 500,000 fetal and neonatal deaths worldwide. Indicators of the situation include elevated blood pressure, diminished placental perfusion, and often seizures. Current medications, akin to those that lower blood pressure in individuals, merely address symptoms rather than tackling the root causes of the issue.
According to Kelsey Swingle, a researcher at the University of Pennsylvania, there are no treatments that effectively address the underlying issue, which lies in the placenta.
Previous research in mice has provided insight into the underlying causes of pre-eclampsia: namely, that the placenta’s inability to produce a critical protein essential for maintaining growth and development contributes to its onset. Characterized by vascular endothelial growth factor deficiency (VEGF), this condition hampers the protein’s functionality, thereby disrupting maternal blood vessel support crucial for placental health.
Restoring the protein could address the root of the issue. The problem is delivering it.
A novel lipid-nanoparticle system capable of immediate and specific targeting of the placenta. In a manner akin to Covid vaccines, where lipid nanoparticles – colloquially referred to as “bubbles” – encapsulate mRNA molecules, which then guide cells to manufacture the requisite protein. While comparable to standard lipid nanoparticles used in mRNA vaccines, these novel bubbles – designated as LNP 55 – exhibit a remarkable 150-fold increase in targeted delivery capabilities.
Two distinct modes of pre-eclampsia were observed to exhibit enhanced vascular endothelial growth factor (VEGF) levels in the placenta following a single dose of therapy, resulting in the proliferation of healthy blood vessels and alleviation of symptoms. No adverse effects were reported on the fetuses following the therapy. Slightly, this initiative has contributed to their development, with the newly born mouse pups demonstrating a healthier weight profile.
The newly developed methodology is a cutting-edge approach.
A Shocking Begin
The initial focus of the group was not on addressing pre-eclampsia.
As the director of our pharmaceutical research centre, we specialise in providing high-quality drug substances to the industry. Despite initial skepticism, his interest was sparked by a flurry of queries from expectant mothers inquiring about the safety of Covid-19 mRNA vaccines for their unborn children.
Covid-19 vaccines comprise two essential components:
The viral genome encodes for a specific strand of messenger RNA (mRNA), which is responsible for synthesizing the spike protein, anchored to the viral surface. Within cells, specialized machinery processes messenger RNA (mRNA), generating proteins that trigger an immediate immune response, effectively alerting the body to the specific virus upon infection.
The opposing half consists of a lipid nanoparticle designed to transport mRNA cargoes safely and efficiently. These innovative lipid vesicles represent significant bioengineering advancements, comprising multiple components that offer versatility and potential applications. Some proteins bind to the mRNA molecule, while others play a role in stabilizing the overall structure. The presence of a moderate amount of LDL cholesterol and various modified lipids appears to diminish the likelihood of immune system aggression.
Prior to administration, researchers found that the vast majority of lipid nanoparticles were directed towards the liver and successfully delivered their payload. The potential to deliver lipid nanoparticles to specific areas of the body beyond the liver is intriguing, as it could enable the targeted delivery of designer therapeutics directly to the organ or tissue of interest, opening up new possibilities for precision medicine.
By leveraging their expertise, the group successfully designed and engineered a tailored lipid nanoparticle with specific affinity for targeting the placenta. Researchers created nearly 100 distinct lipid-based nanoparticles, each boasting a unique formula, and administered them to the bloodstream of pregnant mice, meticulously monitoring their distribution.
A standout candidate, designated as LNP 55, caught our attention. Particles collected in the placenta without being transferred to the fetus remain undistributed. The notion that the fetus is “completely innocent” in pre-eclampsia, uninvolved in triggering this complication, was posited by Thadhani and Karumanchi. This may further minimize any unforeseen consequences on the developing fetus.
Compared to standard lipid nanoparticles, LNP 55 demonstrated a striking 150-fold increased propensity to translocate into various placental cell types, significantly outpacing liver uptake. Can the outcomes obtained from the group questioning indicate that LNP 55 is a viable solution for handling pregnancy-related circumstances?
Load It Up
The subsequent step was identifying the most effective cargo to prevent and treat pre-eclampsia effectively. The researchers isolated VEGF mRNA, potentially enhancing blood vessel development in the placenta.
During pregnancy, researchers observed two distinct forms of pre-eclampsia in mice; a single injection promptly lowered their hypertension, ensuring stable blood pressure until the delivery of their pups. The therapy also reduced the levels of “toxins” released by the damaged placenta.
The discovery holds genuinely exciting implications, suggesting that by reconfiguring blood vessel architecture, we may be on the cusp of achieving long-term therapeutic benefits, according to Dr. Swingle.
The therapy sessions had a positive impact on the developing puppies as well. Mothers diagnosed with pre-eclampsia often deliver babies that are significantly lighter in weight? As a direct consequence of documents inducing early supplies when a mother’s well-being begins to deteriorate. However, an unhealthy placenta also significantly contributes to this issue. While commonplace measures may help address the situation, they do little to alter the initial weight’s trajectory. Due to inadequate nutrients and a scarcity of oxygen, the fetuses appeared remarkably shriveled, as noted by Mitchell.
Studies have shown that pups from mothers administered with VEGF mRNA have exhibited significantly increased size and improved health, mirroring the characteristics of pups born to normal mice without pre-eclampsia, demonstrating a promising therapeutic potential for this treatment approach.
A Lengthy Highway Forward
While potentially effective, there are a few hurdles that need to be addressed before therapy can have its intended impact on pregnant individuals.
While our placentas exhibit significant differences compared to those of mice, particularly in terms of their composition and structure. The group is considering the potential of using guinea pigs, a species that shares a unique characteristic with humans – the presence of placentas in their reproductive process – as a model for future testing purposes. While higher VEGF concentrations might also lead to unforeseen consequences, including increased permeability in blood vessels, this effect was not observed in this study.
One notable limitation of this medication regimen is its dosing schedule. Mice gestate for approximately 20 days, a remarkably brief period compared to the nearly nine months that humans carry their developing offspring. While a single dose showed efficacy in mice, its long-term effects on pregnancy were unclear.
Then there’s timing. Pre-eclampsia typically starts to manifest early in pregnancy, even before the placenta has fully developed. Starting therapy earlier, rather than in the midst of pregnancy, may yield distinctly different results?
Regardless, the research is welcome. Despite significant advances in understanding the complexities of pregnancy, research into pregnancy-related complications has historically trailed behind that devoted to other major health concerns such as cancer, cardiovascular disease, metabolic disorders, and certain rare conditions. While restricted funding may pose a significant challenge, the cultivation of medication specifically designed for expectant mothers faces even greater hurdles due to strict regulations in place to safeguard both mother and fetus.
The newly published study presents a groundbreaking solution for addressing the complex issue of pre-eclampsia, a pervasive and life-threatening condition during pregnancy that urgently requires innovative interventions.
