Novel anti-Mullerian hormone receptor 2 binding peptide prevents chemotherapy-related ovarian follicle loss in a mouse model

Abstract

PURPOSE: Cancer treatments can deplete the ovarian follicle reserve causing infertility and early menopause, with subsequent decline in cardiovascular, cognitive, and overall health. Medical measures to prevent this chemotherapy-induced ovarian damage are currently not available. Anti-Müllerian hormone (AMH) is important for preserving the ovarian follicle pool via downregulation of granulosa cell replication and function. Despite proven therapeutic ability to protect the ovarian follicle number in mice exposed to chemotherapy, AMH is not approved for human use. To overcome this gap, we created and patented a peptide designed to specifically bind to the AMH receptor, AMHR2 binding peptide (AMHR2BP), that could serve as an alternative therapeutic treatment. By activating the same downstream signaling and replicating the biological effects of natural AMH, we sought to investigate whether AMHR2BP could protect the follicle pool in both natural and accelerated ovarian aging mouse models. METHODS: Here, we present a series of in vitro and in vivo translational studies to verify AMHR2BP's affinity, specificity, mechanism of action, stability, and in vivo toxicity and efficacy. We performed immunofluorescence, immunoprecipitation, real-time RT-PCR, mass spectrometry, histological, and immunohistochemistry testing to validate our findings on two levels, gene activation and protein translation. RESULTS: We found that AMHR2BP activates the same SMAD signaling pathways as AMH and ultimately preserves the ovarian follicle pool by preventing the progression of primordial to antral follicles in naturally aging mice. Additionally, we demonstrated that AMHR2BP prevents follicle loss in an accelerated, chemotherapy-induced ovarian aging model, thereby effectively preventing identifiable ovarian damage. Importantly, AMHR2BP also portrays excellent plasma stability with no detectable toxicity. CONCLUSIONS: By mimicking the function of AMH, AMHR2BP represents a new medical therapeutic strategy to preserve fertility and reduce long-term reproductive and health risks from chemotherapy treatments.