MICA: Investigating kisspeptin receptor signalling to improve the treatment of reproductive disease

Kisspeptin is the central controller of reproductive hormone secretion from the hypothalamus. Our group's research has identified a number of reproductive disorders that would benefit from treatment using kisspeptin based therapies. However, there remain many unanswered questions as to how kisspeptin interacts with its receptor. For example, it is known that giving too much kisspeptin can reduce the ability of kisspeptin to induce hormonal stimulation. Additionally, levels of oestrogen at the time of administration can affect the hormonal response to kisspeptin. Moreover, a number of new drugs have been generated that act through the kisspeptin receptor. However, the precise way by which these new kisspeptin based drugs or how oestrogen interacts with the kisspeptin receptor has not been fully described.

Therefore, we will conduct research to understand how natural kisspeptins and newly developed drugs that act on the kisspeptin receptor exert their effects inside cells, how this is altered in times of excessive stimulation, and the effect of changes in oestrogen levels on these processes. In this proposal, we have assembled a team of experts from across the globe to conduct cutting edge experiments to better understand signalling at the kisspeptin receptor. We will work with an industry partner to test an oral kisspeptin based drug that is still in development, as well as other recently developed kisspeptin receptor stimulators. We will use an animal model of hypothalamic amenorrhoea (one of the commonest causes of loss of periods and subfertility) to develop a protocol using a kisspeptin-based therapy that can be used to restore reproductive health.

In summary, it is essential to better understand the action of kisspeptin and kisspeptin-based drugs at the kisspeptin receptor. This work will enable us to develop treatment protocols using kisspeptin or kisspeptin-like drugs that will improve the care of patients suffering from reproductive disorders.

Kisspeptin is a key driver of the reproductive axis by regulating hypothalamic GnRH release. We conducted the first-in-human administration studies of kisspeptin in 2004, and the first clinical trials of kisspeptin as part of assisted reproduction treatment in 2014. However, excessive high dose kisspeptin administration can result in tachyphylaxis, which would impede the use of chronic stimulation protocols to treat conditions of deficient kisspeptin, as part of the pathophysiology of several common hypogonadal disorders such as hypothalamic amenorrhoea (HA). Understanding signalling at the G-protein coupled kisspeptin receptor (KISS1R) to elucidate the mechanism of tachyphylaxis in order to facilitate chronic stimulation protocols, thus represents a major unmet clinical need. We have recently reported that a potent KISS1R agonist, MVT-602, has a markedly prolonged action in healthy and anovulatory women, which is enhanced by oestradiol. These unique properties of MVT-602 are not explained by pharmacokinetics or differences in canonical KISS1R-Gq/11 signalling. Therefore, this project aims to decipher the signal mechanisms induced by KISS1R agonists including novel oral analogues currently in development by our Industry partner, Crinetics. We will also employ unique KISS1R nanobodies that exhibit positive allosteric modulation and investigate distinct spatial-temporal signalling signatures for sustained activation. Critically, how these signal activity profiles, including the actions of oestradiol, modulate GnRH secretion will be assessed in both a human hypothalamic neuronal system derived from pluripotent stem cells and pre-clinical in vivo studies, including therapeutic assessment within a hypogonadal animal model of HA. Overall, we will be able to identify therapeutically desired activity signatures of novel KISS1R modulators to expedite translation of chronic kisspeptin-based treatments in reproductive disorders.