mRNA Therapy Offers Hope for Uterine Factor Infertility
Endometrium-targeted GM-CSF mRNA restored embryo implantation in a preclinical model of uterine dysfunction.
In recent years, women’s health has rightfully gained overdue scientific and public attention. Among the many conditions that have long been understudied is infertility—an emotionally taxing experience in which couples struggle to conceive.
Today, researchers are aiming to expand treatment options beyond assistive reproductive technologies (ART). Although ART has been highly successful in supporting the conception and birth of millions of babies worldwide, the financial, physical, and emotional burden it places on women and couples means it is far from an ideal solution.
In fact, for many couples, it is not a solution at all as it fails to address the root biological causes of their infertility.
Few scientists are as well-positioned to speak to this challenge as Dr. Laura M. Ensign-Hodges, principal investigator and Marcella E. Woll Professor of Ophthalmology at Johns Hopkins Medicine, and Dr. Saed Abbasi, research associate at Johns Hopkins University School of Medicine. In a recent study, Ensign-Hodges and Abbasi explored how endometrium-targeted messenger RNA (mRNA) therapy could directly address uterine factors, which are reported to account for more than 1 in 10 cases of infertility.
Speaking to Technology Networks, Ensign-Hodges and Abbasi shared their motivations for pursuing infertility research and the rationale behind their novel therapeutic strategy.
Unmet needs in infertility treatment drive new research
Despite decades of progress resulting in improved ART success, many patients still endure repeated cycles of invasive, costly, and emotionally demanding procedures. For Ensign-Hodges, this disconnect between technological advancement and patient experience was impossible to ignore.
“I became aware of the tremendous gap in treatment options for infertility through my research and entrepreneurial activities,” she explained. “While the process of ART has certainly evolved and become more effective, it was alarming to me that women often had to go through numerous rounds of painful, expensive, and stressful procedures to get pregnant.”
There are many stages in ART, but Abbasi emphasized that implantation failure remains a dominant barrier to success, occurring in nearly half of all cases. This sparked his interest in directly targeting implantation: “Our new technology can be considered as an add-on to enhance ART and increase the likelihood of success by improving embryo attachment to the endometrium,” he explained.
Stages of ART:
- Ovarian stimulation: Medications are used to stimulate the ovaries to produce multiple eggs.
- Egg retrieval: Eggs are removed from the ovaries using an ultrasound-guided surgical procedure.
- Fertilization: Known as in vitro fertilization (IVF), the eggs are combined with sperm in a laboratory and become embryos once fertilized.
- Embryo testing: Embryos are cultured and monitored frequently, as well as tested for abnormalities.
- Embryo transfer: Selected embryos are placed into the uterus through the vagina using a thin catheter.
The limitations and opportunities of ART
- ART does not address all causes of infertility.
- Implantation failure accounts for nearly half of ART failures.
- Improving endometrial receptivity represents a major therapeutic opportunity.
The role of the endometrium and cytokines in pregnancy and infertility
A successful pregnancy depends on several processes that must align precisely, including implantation.
Regardless of whether conception is assisted or unassisted, implantation of an embryo into the uterine lining, or endometrium, is key. Not only does it anchor the embryo to the uterus, providing the life-sustaining connection between mother and fetus, but implantation also triggers hormonal changes that prevent shedding of endometrium, helping maintain the pregnancy.
For this process to be successful, the uterine lining must be prepared. Abbasi explained: “Normally, the endometrium secretes a wide range of cytokines and hormones that thicken and prepare the endometrium for embryo implantation.” He described how conditions that disrupt the uterine environment can interfere with this process. Even when embryos are viable, implantation may be impaired, leading to a failed pregnancy—a challenge that can persist despite the use of ART.
Inflammatory conditions of the uterus
Trauma, endometriosis, and structural conditions such as fibroids and adhesions, amongst others, can all contribute to uterine inflammation.
Abbasi explained how their therapeutic strategy aims to prepare the uterus for implantation even in the presence of disruption: “Our technology aims to improve endometrial function by restoring secreted cytokines and hormones to normal levels using mRNA encoding for these factors.”
One such cytokine is granulocyte-macrophage colony-stimulating factor (GM-CSF), which is secreted by the fallopian tubes and endometrium during the menstrual cycle. GM-CSF has multiple roles in supporting a healthy pregnancy, and its use within embryo culture media has been shown to improve implantation rates in IVF.
With this in mind, the team hypothesized that delivering GM-CSF to the uterus could support implantation in cases of uterine dysfunction.
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Restoring endometrial receptivity to implantation is key
- Endometrial dysfunction is a major contributor to infertility.
- Numerous conditions can suppress signaling that supports the endometrium in preparing for implantation.
- Restoring this signaling is a viable therapeutic approach.
From model limitations to medical innovation
Instead of delivering therapeutic GM-CSF directly, the team opted to use an alternative approach: mRNA. mRNA is the molecule that carries instructions from DNA to protein-making machinery. Recently, researchers have hijacked this mechanism for therapeutic purposes, realizing that delivering instructions to cells can increase production of desired proteins, such as GM-CSF.
Abbasi explained the rationale behind this approach: “mRNA is like a prodrug; it can only be converted into the therapeutic protein after it is taken up by the target cells.” Therefore, unlike protein infusions, mRNA therapy enables targeted protein production, reducing the risk of systemic distribution and adverse effects.
To achieve this, the mRNA needed to be directed toward and delivered into the target tissue. So, the researchers engineered specialized lipid nanoparticles (LNPs) with surface ligands that selectively bind to endometrial cells, keeping translational potential in mind. “The endometrium in both humans and mice utilizes cell surface proteins called integrins to act as a ‘dock’ for the embryo to attach,” Ensign-Hodges explained. This commonality informed the LNP design and ultimately led to the decision to engineer the transporters to target integrins.
LNPs
LNPs are lipid-based carriers designed to encapsulate and deliver molecules, such as mRNA. They provide a stable transport mechanism that releases therapeutic payloads only once inside cells.
Abbasi added: “Our LNP designs contain a surface signal that acts like a zip code to direct the packaged mRNA specifically to endometrial cells.”
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This dual strategy—combining a “zip code” with a therapeutic parcel—facilitated targeted treatment in the team’s proof-of-concept animal studies. The team observed a sustained increase in GM-CSF expression in the mouse endometrium following infusion of the mRNA-LNP, confirming successful delivery.
Notably, unlike humans, mice do not menstruate. Instead, they have an estrous cycle—a recurring, hormone-driven process in which the uterine lining thickens and is later reabsorbed rather than shed.
Despite this difference, Ensign-Hodges highlighted key similarities: “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.”
Precision mRNA therapy, put simply
- mRNA delivery enables customizable, functional protein production.
- LNPs provide a delivery system that can be engineered to target specific tissues.
- Precision mRNA therapy can deliver what you want, where you want it.
Uterine-targeted GM-CSF mRNA therapy for infertility
Next, the team tested the approach in a mouse model of uterine dysfunction, which reduced both endometrial thickness and the number of implantation sites to investigate whether the infusion had therapeutic benefits.
In the treatment group, embryo implantation was restored to levels comparable to those seen in healthy mice. At the same time, untreated mice showed a marked reduction in implantation sites, averaging 67%. Importantly, no evidence of toxicity was observed in the treated mice.
Nowhere are the longstanding effects of the historical “male-as-default” research approach more evident than in women’s health, and this is a challenge that Ensign-Hodges acknowledged. However, she highlighted the value of using an established ethanol-induced injury mouse model in their research. She also noted that Abbasi carefully validated various aspects of the preclinical model, including structural uterine damage, implantation failure, and nanoparticle LNP uptake, to maximize translational potential.
Better models mean better medicines
- Model validation can reveal key inter-species insights that inform drug design and delivery.
- Robust preclinical models support translation into humans.
- Researchers are working to narrow gaps in models crucial for women’s health research.
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Expanding the scope of mRNA therapeutics in women’s health
Abbasi described the modular nature of mRNA as a fundamental advantage. “Now, we can change the mRNA sequence to provide instructions for making an endless list of therapeutic proteins,” he explained.
“mRNA technology is like changing pizza toppings when you need a new therapeutic protein, rather than remaking the entire dish from scratch.” — Dr. Saed Abbasi
Future studies will need to confirm that endometrial targeting remains precise when this approach is used in humans, and the optimal therapeutic protein may vary depending on the indication.
Beyond infertility, both researchers envisioned broad applications. “Our technology can be explored to treat other endometrial disorders, not only infertility, but also endometrial cancers and painful conditions such as endometriosis,” Abbasi stated.
Ensign-Hodges added, “There are many unmet needs in women’s health, and research and technology development often lag behind in these areas. I am particularly excited about the potential to treat a range of conditions and disorders that affect the endometrium.”
On Women’s Health Awareness Day, this research highlights how endometrium-targeted mRNA delivery could expand infertility treatment and provide a basis for treating an array of gynecological conditions.
- Implantation failure remains among the dominant causes of infertility.
- Targeted mRNA delivery enables localized, customizable therapy.
- Innovation in women’s health research is accelerating, but there is more work ahead.
This content includes text that has been created with the assistance of generative AI and has undergone editorial review before publishing. Technology Networks' AI policy can be found here.
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