New research seeks an mRNA therapy for heavy menstrual bleeding
Every minute in the U.S., a woman requires a blood transfusion because of her period. “Heavy menstrual bleeding affects one in three women, but our resources for treating it are incredibly limited,” said Kathleen O’Neill, MD, an assistant professor of Obstetrics and Gynecology and the program director of the Uterine Transplant Program at the University of Pennsylvania.
That may be about to change, thanks to a new research program O’Neill is leading to develop a new type of mRNA therapy—a platform that can be used to explore the underlying causes of abnormal uterine bleeding and also to treat it.
Heavy menstrual bleeding regularly interferes with everyday life, causing women to miss school or work and potentially leading to adverse health conditions like anemia. Heavy periods can also indicate health issues such as uterine fibroids, thyroid disease, bleeding disorders, and pituitary tumors. Yet this all-too-common symptom is often overlooked by health care professionals. No clear measure or marker exists to define what constitutes “normal” bleeding, and many women with heavy menstrual bleeding don’t even realize their cycles aren’t typical.
The new effort is funded through The Missed Vital Sign, a women’s health program launched by Wellcome Leap to accelerate breakthroughs in understanding and treating heavy menstrual bleeding, that will provide the team up to $5 million. Co-investigators on the project include Jillian Melamed, PhD, a research assistant professor of Infectious Diseases at Penn, Kara McKinley, PhD, an assistant professor of Stem Cell and Regenerative Biology at Harvard University, and Kelsey Swingle, PhD, an assistant professor of Bioengineering at Rice University.
Through The Missed Vital Sign program overall, Wellcome Leap will invest $50 million in research to better quantify heavy menstrual bleeding, understand its causes, develop new treatments, and raise awareness among the public and health care providers about what normal menstrual bleeding is and isn’t. “The beauty of this program is that it’s trying to attack menstrual bleeding on all fronts,” O’Neill said.
Currently, treatments for heavy menstrual bleeding are limited. When bleeding is related to uterine fibroids, surgery to remove the fibroids can help to reduce menstrual flow. Patients with heavy periods may also benefit from hormonal interventions like birth control pills or an intra-uterine device (IUD), which thins the endometrial lining to reduce bleeding. Yet surgery and hormones can have significant risks and side effects, and they aren’t right for every woman.
Understanding the endometrium and the biology of heavy periods
As a physician-scientist in obstetrics and gynecology, O’Neill has a special interest in understanding the uterus and its inner lining, or endometrium. Dysfunction of the endometrium is associated with a host of problems, including abnormal bleeding, cancer, infertility, and pregnancy loss. Despite its importance, she says, “the endometrium has been like a black box. We still don’t understand many of the fundamental questions about how it works.”
O’Neill, Melamed and their collaborators plan to develop a new type of treatment: a vaginal gel made of lipid nanoparticles that will deliver mRNA to the endometrial tissue in order to restore the production of proteins that are critical in limiting menstrual bleeding. Treatments based on mRNA gained fame for their role in developing COVID vaccines, but they have shown promise for treating a variety of diseases, from autoimmune diseases to cancers to cystic fibrosis. With this new therapy, the researchers plan to extend the use of lipid nanoparticle delivery of mRNA to the field of women’s health to reduce heavy menstrual bleeding.
Previous research has singled out some of the biological pathways that may play a role in heavy periods, O’Neill said. One such pathway is vasoconstriction, the process that causes blood vessels to narrow to reduce blood flow. Another is proliferation repair, a process involved in regenerating new tissue during wound healing—and which plays a role in the monthly breakdown and renewal of the endometrium. Data from past studies in both animals and humans has pinpointed genes and proteins involved in these pathways that appear to be present at lower or higher levels in women with heavy menstrual bleeding.
The promise of mRNA
The mRNA platform made potent COVID-19 vaccines possible was invented at Penn Medicine. Now, the technology represents a multi-use tool that could lead to new, lower-cost vaccines and treatments for virtually any human disease.
Preclinical research to explore a future non-hormonal treatment
O’Neill, Melamed and their colleagues aim to develop a vaginal gel that would deliver mRNA into the endometrium to regulate those proteins. Initially, the team will test the treatment in samples of human endometrial tissue and mouse models that have been specially engineered to have menstrual cycles that mimic those of human women. If the treatment appears successful in those preclinical studies, the researchers hope to eventually test the safety and efficacy of an mRNA vaginal gel in clinical trials.
“This is just the first step. But the hope is that we can eventually develop a new therapy for heavy menstrual bleeding that isn’t hormonal, doesn’t require surgery, and can be easily administered at home,” O’Neill said.
Yet even if those first protein targets don’t succeed in reducing heavy periods, having a medication that safely delivers mRNA to the uterus would serve as a valuable tool for testing future protein targets as scientists continue to learn more about the diverse causes of heavy menstrual bleeding. “One of the benefits of The Missed Vital Sign program is that we have all these fellow collaborators who are trying to better understand what’s causing abnormal bleeding. As they make new discoveries, we can test them in our model to see whether a particular protein is having a clinical effect,” O’Neill said.
O’Neill is eager to find solutions to this pressing problem, in line with the ambitious goal of The Missed Vital Sign: to reduce the time it takes a woman to get effective treatment for heavy menstrual bleeding, from the current average of five years to just five months. “It’s a lofty goal, but we’re trying to make an impact on a big problem—and one that has gotten insufficient attention,” O’Neill said. “Good science needs to be rigorous, but it sometimes moves too slowly. We have big ideas and want to move things along with a sense of urgency.”