ECE2023 Oral Communications Oral Communications 7: Pituitary and Neuroendocrinology 2 (6 abstracts)
Investigating intranasal kisspeptin as a novel, effective and preferable route of delivery using human, rodent and pharmaceutical models
Edouard G Mills 1 , Magda Swedrowska 2 , Virginia Delli 3 , Konstantina Chachlaki 3 , Mauro Sérgio 3 , Laurine Decoster 3 , Gaetan Ternier 3 , Layla Thurston 1 , Maria Phylactou 1 , Bijal Patel 1 , Lisa Yang 1 , Sophie Clarke 1 , Beatrice Muzi 1 , Emma Alexander 1 , Muhammad Choudhury 1 , Paul Bech 1 , Ali Abbara 1 , Ben Forbes 2 , Paolo Giacobini 3 , Vincent Prevot 3 , Alexander Comninos 1 & Waljit Dhillo 1
1Imperial College London, Section of Endocrinology and Investigative Medicine, London, United Kingdom; 2King’s College London, Institute of Pharmaceutical Science, London, United Kingdom; 3Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, Lille, France
Background: Kisspeptin is a critical activator of hypothalamic GnRH neurons and is essential for reproductive health. Emerging data reveals that kisspeptin-based therapeutics have substantial potential to treat reproductive, psychosexual and bone disorders. However, current delivery is limited to the subcutaneous or intravenous routes, presenting barriers to development. Alternative routes of administration would overcome this and capitalise on the benefits of kisspeptin-based therapies. To address this, we comprehensively investigated the therapeutic potential of intranasal kisspeptin administration for the first time using a series of human, rodent and pharmaceutical studies.
Methods: Human studies: Healthy men (n=12) and a patient group of women with hypogonadism (due to Hypothalamic Amenorrhoea [HA], n=5) completed a randomised, double-blind, crossover, placebo-controlled study investigating the acute effects of intranasal kisspeptin-54 administration vs 0.9% saline placebo. After monitored self-administration of intranasal kisspeptin (doses: 3.2-25.6 nmol/kg [healthy men] and 12.8 nmol/kg [women with HA]) or placebo, plasma kisspeptin and serum reproductive hormones were measured every 15mins for 4hrs. Next, we undertook rodent studies in adult C57BL/6J male mice to elucidate the putative mechanism by which intranasally administered kisspeptin can stimulate reproductive hormone release, using intranasal delivery of fluorescently-tagged kisspeptin-54 and a series of c-Fos experiments. Thereafter, we conducted pharmaceutical studies to characterise the chemical stability of kisspeptin-54 in solution for nasal delivery in real-time.
Results: Human studies: in healthy men, intranasal kisspeptin rapidly and dose-dependently increased plasma kisspeptin at doses 6.4-25.6 nmol/kg (P<0.01 for all doses vs placebo), with peak rises within 15-30 minutes. In parallel, intranasal kisspeptin acutely and robustly increased serum LH at doses 6.4-25.6 nmol/kg (P<0.01 for all doses vs placebo) with peak rises at 30 minutes. Similarly, in patients with HA, intranasal kisspeptin acutely increased plasma kisspeptin (P=0.004 vs placebo) and serum LH (P=0.004 vs placebo). Animal studies: To provide mechanistic insight, we demonstrate in male mice that GnRH neurons located in the olfactory bulb express kisspeptin receptors and that intranasal delivery of fluorescently-tagged kisspeptin-54 binds to the olfactory epithelium. Pharmaceutical studies: Kisspeptin-54 in 0.9% saline remained within pharmaceutically accepted limits for stability for up to 60 days at 4°C revealing realistic pharmaceutical potential.
Conclusion: We demonstrate robust clinical effects in both healthy volunteers and patients with hypogonadism and provide mechanistic and pharmaceutical evidence for intranasal delivery as a novel, non-invasive and effective kisspeptin administration route for the management of reproductive disorders that would be preferable to patients and clinicians alike and so transform the ongoing development of kisspeptin-based therapeutics.
Volume 90
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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