Research Overview
Researchers at Johns Hopkins Medicine developed a method for delivering therapeutic messenger RNA (mRNA) to the uterine lining (endometrium) in mice using modified lipid nanoparticles (LNPs). Published in Nature Nanotechnology on January 19, their findings in an endometrial injury model indicate an improvement in embryo implantation, suggesting a potential new treatment for certain types of infertility. The study was funded by the National Institutes of Health.
Targeted Delivery
The research demonstrated the ability to precisely deliver therapeutic mRNA, which provides cells with instructions to produce specific proteins, to damaged uterine linings for a controlled duration. Conditions like endometriosis and Asherman syndrome can lead to infertility by hindering embryo attachment to the endometrium, a crucial step for pregnancy, even with assisted reproductive technologies (ART). Laura Ensign, Ph.D., principal investigator at Johns Hopkins Medicine, noted that patients unable to achieve or sustain pregnancy with ART currently lack effective FDA-approved treatments.
mRNA therapies instruct cells to produce specific functional proteins without altering DNA. A challenge in developing mRNA therapeutics is ensuring precise delivery to the target site at effective concentrations while minimizing systemic toxicity. Saed Abbasi, Ph.D., the lead author, stated that the experiments aimed to determine the feasibility of delivering fragile mRNA molecules to the endometrium via LNPs and to identify conditions that could be improved.
Methodology and Results
To protect mRNA from degradation, researchers used an LNP delivery system to carry mRNA encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune protein thought to enhance embryo attachment by thickening the endometrium. Recombinant GM-CSF protein has limitations due to its short half-life and potential for off-target effects.
Initial experiments involved administering GM-CSF mRNA to mouse endometrium via intrauterine infusion. Conventional mRNA-LNPs were observed to spread beyond the delivery site, causing liver and spleen toxicity. To reduce off-target delivery, researchers modified LNPs with an RGD peptide, which targets integrins expressed on the endometrium during the window of implantation (WOI). This modification enhanced targeted delivery, therapeutic benefits, and reduced side effects when infused during the WOI.
Following infusion with the tailored mRNA-LNP, GM-CSF protein expression in the mouse endometrium remained elevated for up to 24 hours, peaking nearly threefold higher at eight hours compared to recombinant GM-CSF protein infusion. Blood GM-CSF levels were sixtyfold lower in the mRNA-LNP group, suggesting an improved safety profile and reduced organ toxicity risk.
Future Implications
Ensign stated that the window of implantation is comparable between mice and humans, suggesting the findings could be applicable to other model systems. In a mouse model of endometrial injury, the tailored mRNA-LNP treatment restored embryo attachment to levels seen in healthy mice, while untreated mice exhibited 67% fewer implantation sites. No toxicity was observed in the uterus or other organs of the treated mice.
Future experiments will involve using the LNP delivery system to evaluate other molecules for fertility improvement. The researchers also anticipate the system could address other endometrial disorders like endometriosis and endometrial cancer.
The study received funding from the National Institutes of Health and other institutions. Saed Abbasi, Justin Hanes, and Laura M. Ensign are inventors on a related patent application.