mRNA Nanoparticles Offer New Hope for Female Infertility Treatment

A key step in achieving a successful pregnancy is the implantation of a viable embryo in the endometrial lining of the uterus. Normally, the endometrium secretes a wide range of cytokines and hormones that thicken and prepare it for embryo implantation. These factors can be lacking or reduced when there is infection or inflammation.

Our technology aims to improve endometrial function by restoring secreted cytokines and hormones to normal levels using mRNA encoding for these factors. 

First, we used mRNA instead of the standard form of protein infusions (i.e., recombinant proteins). mRNA is like a prodrug; it can only be converted into a therapeutic protein after it is taken up by the target cells. This will naturally reduce protein levels in body parts without cells, such as bodily fluids, making systemic drug distribution and adverse effects lower.

Second, our LNP designs contain a surface signal that acts like a zip code to direct the packaged mRNA specifically to endometrial cells. Taken together, mRNA was specifically delivered to endometrial cells by LNPs, where the mRNA was converted to therapeutic protein only inside endometrial cells with much-reduced access to other tissues.

While it is often true that we are limited by the preclinical models and tools available to validate new therapeutics, this is particularly true in many areas of women’s health. However, we were fortunate to have a prior report of the ethanol-induced injury model in mice, which was a model of thin endometrium.

Abbasi was very careful about validating the model, including characterizing the change in endometrial structure and the reduction of successful embryo implantation, while also ensuring that his LNPs were able to successfully deliver mRNA to the damaged endometrium. There are obviously differences in the structure of the uterus and the function of the endometrium in mice. However, the endometrium in both humans and mice utilizes cell surface proteins called integrins to act as a “dock” for the embryo to attach, which is why Abbasi engineered the LNPs to bind to integrins. Further, he was conscientious about scouring the literature to determine when integrin expression in humans was most closely mimicked in mice, and to design experiments with the highest likelihood of translation to human biology.

The human and mouse endometria are very similar in structure, and both undergo hormone-dependent remodeling. Like humans, the mouse endometrium decidualizes to prepare for embryo implantation, and many of the cellular markers that are expressed are conserved between the two species. Thus, while the mouse estrous cycle is much shorter than the menstrual cycle and does not include menstruation, there are many structural and functional similarities, making the mouse a commonly used model for endometrial research.

Now, we can change the mRNA sequence to provide instructions for making an endless list of therapeutic proteins. Although our study focused on delivering GM-CSF mRNA, some patients may benefit more from other types of cytokines, growth hormones, or a personalized combination. This is a huge advantage of using mRNA over recombinant proteins, in which each protein must be synthesized and extensively purified before it can be dosed in humans.

mRNA technology is like changing pizza toppings when you need a new therapeutic protein, rather than remaking the entire dish from scratch as you would with recombinant proteins.

Additionally, our technology can be explored to treat other endometrial disorders, not only infertility, but also endometrial cancers and painful conditions such as endometriosis.