Potential new mRNA-based treatments for pre-eclampsia

A single injection of a therapeutic candidate was associated with improvements in maternal blood pressure in two mouse models.

In a recent study published in naturescientists at the University of Pennsylvania have investigated a new approach to treating preeclampsia, a severe and often life-threatening pregnancy disorder, using lipid nanoparticles. vascular endothelial growth factor (VEGF) delivers messenger ribonucleic acid (mRNA) directly to the placenta. The goal of this method was to restore vascular health, reduce high blood pressure, and improve fetal outcomes.

background

Preeclampsia affects 3% to 5% of pregnancies worldwide and contributes significantly to maternal and fetal morbidity. It usually manifests as gestational hypertension caused by placental insufficiency. During normal pregnancy, trophoblast cells are cells that help the embryo attach to the uterine wall, rebuild the uterine arteries, and ensure adequate blood flow. In preeclampsia, impaired arterial remodeling leads to placental hypoxia, leading to the release of antiangiogenic factors such as soluble FMS-like tyrosine kinase-1 or sFlt-1, which reduce VEGF activity and promote hypertension. It will be.

Current treatments focus on managing symptoms rather than addressing the root cause, often promoting premature birth as the only underlying treatment. Furthermore, approaches such as recombinant VEGF protein, gene silencing, and viral vector therapy have demonstrated potential to target placental dysfunction, but delivery efficiency, immunogenicity, limited stability, etc. factors hinder clinical application.

However, recent advances in lipid nanoparticles (LNPs) have shown success in vaccine delivery and offer the potential to overcome these limitations in targeting placental disorders such as pre-eclampsia.

About research

In this study, we utilized advanced LNP technology to deliver VEGF mRNA to the placenta and target the underlying dysfunction of preeclampsia. The researchers screened 98 LNP formulations using high-throughput barcoding and identified 55 LNPs that were placenta-specific candidates. This formulation is β2-glycoprotein I (β2-GPI)-based targeting mechanism.

This LNP-55 was encapsulated with VEGF mRNA and tested in two mouse models of preeclampsia: an inflammation-induced model and a hypoxia-induced model. Pregnant mice received a single intravenous injection of LNP 55 on day 11.5 of gestation. The biodistribution of LNP-55 was evaluated using luminescence and fluorescence imaging.

The researchers also used flow cytometry and histological staining to analyze cell delivery to the placenta and other maternal tissues. Additionally, maternal blood pressure and fetal health were monitored until late pregnancy, and their effects on immunomodulation and placental angiogenesis were also investigated.

The effects of the formulation on systemic markers including serum VEGF and sFlt-1 levels were determined after treatment. Additionally, the researchers evaluated the effects on cytokines and liver enzymes to assess treatment efficacy and safety. Comparisons with industry standard LNPs were used to validate the specificity and efficacy of LNP 55 in targeted placental delivery.

This study also investigated β2-GPI adsorption as a potential mechanism that may enable placental tropism and performed knockdown experiments to understand further targeting dynamics. The researchers also carefully avoided off-target effects, ensuring a safety profile suitable for potential clinical applications.

result

This study found that LNP-55 efficiently delivered VEGF mRNA to the placenta and significantly reduced antenatal symptoms.Symptoms of eclampsia In a mouse model. Treated mice showed restored maternal blood pressure and improved fetal outcomes.

In a proinflammatory model, LLP 55-mediated delivery of VEGF mRNA normalized hypertension and increased fetal weight compared to untreated controls. Similarly, the placental vasculature also showed improved vascular density and an effective therapeutic effect.

Decreased levels of the anti-angiogenic marker sFlt-1 were also observed in serum, indicating increased VEGF availability. Additionally, this treatment improved systemic immune responses by reducing inflammatory cytokines such as interleukin (IL)-6 and interferon gamma (IFN-γ), which are elevated in preeclampsia.

In hypoxia-induced model, LNP-55 effectively reduced maternal hypertension and enhanced placental function. Although blood pressure reduction was also observed with alternative formulations, LNP 55 was successful in maintaining normal blood pressure for an extended period of time.

Placental histology results also confirmed partial recovery of vascular structures. Furthermore, serum analysis revealed that sFlt-1 levels were significantly reduced while VEGF levels were optimized without causing deleterious increases in liver enzymes.

Additionally, flow cytometry findings demonstrated targeted delivery of VEGF mRNA to placental trophoblast cells and immune cells essential for vascular repair. This study also showed minimal off-target effects, particularly reduced delivery to splenic immune cells in a preeclampsia model.

Overall, the results of this study demonstrate that placenta-specific VEGF mRNA delivery is a viable therapeutic strategy to treat preeclampsia, and that addressing the root cause rather than simply managing the symptoms could significantly improve existing interventions. suggested that it offers many advantages compared to

conclusion

In summary, this study demonstrated the potential of LNP 55 to deliver VEGF mRNA to the placenta and effectively treat preeclampsia in a mouse model. This therapy was found to alleviate maternal hypertension, restore placental function, and improve fetal outcomes while minimizing off-target effects. These results represent a significant advance in targeted RNA-based therapies and lay the foundation for future clinical research to combat preeclampsia and improve maternal and child health worldwide.