Ovarian somatic organoids as a drug discovery model for reproductive longevity

The National Institute of Child Health and Human Development awarded Northwestern University $240,000 on September 1, 2026, under the Child Health and Human Development Extramural Research Projects program (CFDA 93.HDR) to develop ovarian somatic organoids as a drug discovery model for reproductive longevity.

The research addresses ovarian aging, characterized by loss of egg quantity and quality leading to infertility and altered endocrine function. The funded work builds on the recipient's discovery that aging ovaries develop fibrosis—excess accumulation of extracellular matrix proteins accompanied by inflammation—which impairs follicle development, egg quality, and ovulation. The team demonstrated that treatment of mice with a low-dose FDA-approved anti-fibrotic drug prevented age-associated fibrosis and inflammation while improving ovarian function, including follicle number, ovulation events, hormone production, and estrous cyclicity. This project will translate these fundamental mechanisms into therapeutic interventions to extend ovarian function and improve reproductive decision-making, quality of life, and overall healthspan for women.

The award supports work performed at Northwestern University's Chicago, Illinois location through August 31, 2028. The funding is classified as a Project Grant, an assistance type under NICHD's extramural research program supporting investigator-initiated basic and clinical research in child health and human development domains.

Abstract

The female reproductive system ages in otherwise relatively young individuals; fertility begins to decline in women in their mid-thirties and reproductive function ceases at menopause around age fifty. Ovarian aging is characterized by a loss of EGG quantity and quality which translates into decreased fertility and endocrine function. Ovarian aging has broad societal ramifications as more women delay childbearing and experience infertility. Moreover, due to health advances, women are living well post-menopause in an altered hormone milieu which can negatively impact sexual, cardiovascular, immune, bone, and cardiac health. Thus, there is a critical need to translate fundamental mechanisms of ovarian aging into therapeutic interventions that can extend ovarian function to align with modern lifestyles and improve reproductive decision-making, quality of life, and overall healthspan for women. We discovered that the aging ovary becomes stiff with age due to a process known as fibrosis which is accompanied by inflammation and refers to the excess accumulation of certain extracellular matrix (ECM) proteins. The fibrotic ovary negatively affects follicle development, EGG quality, and ovulation, and IT provides a suitable niche for ovarian cancer. Thus, there is a strong rationale for using anti- fibrotic agents to soften the ovary and prolong its normal function. In fact, we demonstrated that treatment of mice with a low dose FDA-approved anti-fibrotic drug prevented age-associated fibrosis and inflammation while simultaneously improving ovarian function with respect to follicle number, ovulation events, hormone production, and estrous cyclicity. These findings provide important proof-of-concept that ovarian fibrosis can be modulated pharmacologically to improve reproductive outcomes, but while this particular drug was not toxic in mice, IT causes liver toxicity in human and would be contraindicated for chronic use. Thus, there is a critical need to identify novel anti-fibrotic drug targets that are functional in the ovary and can advance to clinical trials for ovarian aging. A major limitation, however, has been the lack of adequate EX vivo models that faithfully recapitulate the cellular heterogeneity and function of the ovarian microenvironment. We recently engineered an innovative organoid system to model the ovarian somatic compartment and the aging pro-fibrotic response outside the body. Here we will test the overarching hypothesis that this engineered ovarian somatic organoid model can be harnessed to establish a preclinical drug discovery pipeline for compounds that target ovarian fibrosis. We will use this ovarian somatic organoid model as a complex phenotypic assay in a tiered drug screen of a commercially available library of anti-fibrotic compounds assessing biological efficacy, toxicity, and specificity. The particular endpoints for biological efficacy include the fibrotic response (aim 1), ECM dynamics (aim 2), and cellular stiffness (aim 3). This research is a necessary first step to translate foundational knowledge on the aging ovarian microenvironment into therapeutic strategies benefiting both fertility and endocrine function. Moreover, because fibrosis is a hallmark of aging tissues, our discoveries in the ovary may inform fibrosis more broadly.