Metastin (also known as kisspeptin) is a protein that combines with the G protein–coupled receptor GPR54 to trigger the secretion of gonadotropin-releasing hormone (GnRH), which stimulates the pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Metastin has a critical role in triggering puberty and in regulating ovulation and other vital aspects of fertility and reproduction. The researchers are developing metastin as a therapy for conditions such as infertility, delayed puberty, the absence of menstruation (called amenorrhea) and reproductive cancers.
The goal of this proposal is to obtain financial support for Investigational New Drug (IND)–directed preclinical toxicology studies to facilitate the administration of metastin, the ligand for a G protein–coupled receptor, GPR54, to humans.
Two years ago, our research team identified the critical role of GPR54 in the initiation of puberty across mammalian species. Since GPR54 was found to be a regulator of GnRH secretion in both mice and men, attention has subsequently focused on the biologic role of its ligand, metastin. Metastin administration in vivo has been demonstrated in several species to be an exceptionally powerful stimulant of GnRH release, and by extension, LH secretion. In fact, it is the most potent peptide with respect to stimulating GnRH secretion ever studied to date.
As a signal for GnRH release, understanding the role of metastin has far-reaching biologic and therapeutic applications. Our research group is deeply invested in exploring the physiology of metastin using human models. However, to proceed with human studies, we need to perform preclinical toxicology to file an investigator-initiated IND.
Massachusetts General Hospital, Boston
Stephanie Seminara, M.D.
William Crowley, M.D.
Public Health Impact
Metastin is a robust stimulus for GnRH release, and its administration can modulate the onset of sexual maturation in animals. If exogenous GnRH can stimulate the pituitary and GnRH analogues/antagonists can down-regulate or block GnRH receptors, metastin (or analogous compounds) may act comparably with respect to the receptor GPR54 and provide another avenue for therapeutic intervention for patients with reproductive cancers, infertility, amenorrhea and pubertal delay.
Work on this project is complete. The investigator successfully filed an IND application using BrIDGs data and initiated clinical testing.
- Bioanalytical method development
- Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies
- Investigational New Drug (IND)-directed toxicology