Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders

Ali Abbara, Pei Chia Eng, Maria Phylactou, Sophie Clarke, Rachel Richardson, Charlene M Sykes, Chayarndorn Phumsatitpong, Edouard Mills, Manish Modi, Chioma Izzi-Engbeaya, Debbie Popadopoulou, Kate Purugganan, Channa N Jayasena, Lisa Webber, Rehan Salim, Bryn Owen, Paul Bech, Alexander N Comninos, Craig A Mcardle, Margaritis VoliotisKrasimira T Tsaneva-Atanasova, Suzanne Moenter, Aylin Hanyaloglu, Waljit S Dhillo

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

BACKGROUND. Kisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.

METHODS. We conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.

RESULTS. In healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).

CONCLUSION. Taken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.
Original languageEnglish
Pages (from-to)6739–6753
Number of pages15
JournalJournal of Clinical Investigation
Volume130
Issue number12
Early online date16 Nov 2020
DOIs
Publication statusPublished - 1 Dec 2020

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