A single injection of the therapeutic candidate was associated with improvements in maternal blood pressure in two mice models.
In a recent study published in Nature, University of Pennsylvania scientists investigated a novel approach for treating pre-eclampsia, a severe and often life-threatening pregnancy disorder, by using lipid nanoparticles to deliver vascular endothelial growth factor (VEGF) messenger ribonucleic acid (mRNA) directly to the placenta. The goal of the method was to restore vascular health, alleviate hypertension, and improve fetal outcomes.
Background
Pre-eclampsia impacts 3%–5% of pregnancies globally, significantly contributing to maternal and fetal complications. It typically manifests as gestational hypertension caused by placental dysfunction. During normal pregnancies, trophoblasts are the cells that help the embryo attach to the uterine wall, remodel uterine arteries, and ensure sufficient blood flow. In pre-eclampsia, impaired arterial remodeling leads to placental hypoxia and the release of antiangiogenic factors, including soluble fms-like tyrosine kinase-1 or sFlt-1, which reduces VEGF activity and promotes hypertension.
Current treatments focus on managing symptoms rather than addressing root causes and often promote preterm delivery as the only definitive cure. Furthermore, while experimental approaches, including recombinant VEGF proteins, gene silencing, and viral-vector therapies, have demonstrated potential in targeting placental dysfunction, factors such as delivery efficiency, immunogenicity, and limited stability have hindered their clinical application.
However, recent advances in lipid nanoparticles (LNPs), which have shown success in the delivery of vaccines, indicate a potential to overcome these limitations in targeting placental disorders such as pre-eclampsia.
About the study
The present study utilized advanced LNP technology to deliver VEGF mRNA to the placenta, targeting the underlying dysfunction in pre-eclampsia. The researchers screened 98 LNP formulations using high-throughput barcoding to identify a placenta-specific candidate, LNP 55. This formulation demonstrated enhanced mRNA delivery to the placenta using a β2-glycoprotein I (β2-GPI)-based targeting mechanism.
This LNP 55 was encapsulated with VEGF mRNA and tested in two mouse models of pre-eclampsia — an inflammation-induced model and a hypoxia-induced model. Pregnant mice received a single intravenous injection of LNP 55 on gestational day 11.5. The biodistribution of LNP 55 was assessed using luminescence and fluorescence imaging.
The researchers also analyzed the cellular delivery to placental and other maternal tissues using flow cytometry and histological staining. Additionally, maternal blood pressure and fetal health outcomes were monitored until late pregnancy, while the effects on immune modulation and placental vascularization were also examined.
The impact of the formulation on systemic markers, including serum VEGF and sFlt-1 levels, was measured post-treatment. Additionally, the researchers evaluated the effects on cytokines and liver enzymes to assess therapeutic efficacy and safety. Comparisons with industry-standard LNPs were used to validate the specificity and potency of LNP 55 in targeted placental delivery.
The study also explored β2-GPI adsorption as a potential mechanism that might be enabling placental tropism and conducted knockdown experiments to understand further targeting dynamics. The researchers also carefully avoided off-target effects and ensured safety profiles suitable for potential clinical translation.
Results
The study found that LNP 55 efficiently delivered VEGF mRNA to the placenta, significantly reducing pre-eclampsia symptoms in mouse models. The treated mice exhibited restored maternal blood pressure and improved fetal outcomes.
In the inflammation-induced model, the delivery of VEGF mRNA through LLP 55 normalized hypertension and increased fetal weights compared to untreated controls. Similarly, placental vasculature showed improved blood vessel density, indicating effective therapeutic action.
Reduced levels of the antiangiogenic marker sFlt-1 were also observed in serum, indicating increased VEGF availability. Additionally, the therapy improved systemic immune responses by reducing inflammatory cytokines such as interleukin (IL)-6 and interferon-gamma (IFN-γ), which are elevated in pre-eclampsia.
In the hypoxia-induced model, LNP 55 effectively alleviated maternal hypertension and enhanced placental function. Although blood pressure reductions were also observed with alternative formulations, LNP 55 was successful in maintaining long-term normal blood pressure.
Placental histology results also confirmed partial restoration of vascular architecture. Furthermore, the serum analysis revealed that sFlt-1 levels decreased significantly, while VEGF levels were optimized without inducing adverse liver enzyme elevations.
Additionally, the flow cytometry findings indicated targeted delivery of VEGF mRNA to placental trophoblasts and immune cells, which are essential for vascular repair. The study also indicated minimal off-target effects, especially reduced delivery to spleen immune cells in pre-eclampsia models.
Overall, the findings suggested that placenta-specific VEGF mRNA delivery is a viable therapeutic strategy for treating pre-eclampsia and offers numerous benefits over existing interventions by addressing the root causes rather than merely managing symptoms.
Conclusions
To summarize, the study demonstrated the potential of LNP 55 for delivering VEGF mRNA to the placenta and effectively treating pre-eclampsia in mouse models. The therapy was found to alleviate maternal hypertension, restore placental function, and improve fetal outcomes with minimal off-target effects. These results mark a significant advancement in targeted RNA-based therapeutics, providing a foundation for future clinical research to combat pre-eclampsia and enhance maternal-fetal health worldwide.
