Periodic Reporting for period 1 - GRASP (Antagonizing GnRH signaling as a “holistic” therapeutic strategy for Polycystic Ovary Syndrome)
Okres sprawozdawczy: 2023-09-01 do 2025-02-28
Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition, affecting up to 18% of women worldwide, and characterized by a range of endocrine, reproductive, and metabolic abnormalities. As the origin of PCOS remains largely unknown, there is neither a cure nor mechanism-based treatments leaving patient management suboptimal and focused solely on symptomatic treatment. The condition was originally classified as a reproductive disorder as it represents the most common cause of anovulatory infertility in women. Today, it is well known that PCOS has other long-term health repercussions, including obesity, metabolic syndrome and type-2 diabetes. As a consequence, the syndrome has a significant impact on the quality of life and represents an economic burden for patients and society. There is thus an urgent need to design effective therapeutic strategies aimed at curing and/or alleviating the reproductive and metabolic health-related burden of women with PCOS.
The international evidence-based guideline for the assessment and management of PCOS endorses the use of the Rotterdam diagnostic criteria, where a woman must have 2 out of the following 3 criteria for the diagnosis to be reached: sporadic or absent ovulation (oligo-anovulation, OA), biochemical or clinical evidence of hyperandrogenism (HA), and polycystic ovarian morphology (PCOM). HA is a common feature among women with PCOS, affecting nearly 80% of women diagnosed using the Rotterdam definition, which significantly contributes to the OA. The key neuroendocrine aberration in women with PCOS is increased luteinizing hormone (LH) pulse frequency, documented in 75 % of women with PCOS, regardless of their body mass index (BMI). This suggests an increase in activity of gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus. GnRH neurons are the master regulators of reproductive functions in mammals as they control fertility by driving the secretion of LH, and follicle-stimulating hormone (FSH) from the pituitary gland. These factors regulate the development and functions of the gonads in all vertebrates. In women with PCOS, the LH hyper-pulsatility contributes to increased ovarian thecal androgen secretion and failure of ovulation, constituting a pivotal pathogenic role in the syndrome. These evidences suggest that deregulation of GnRH neuronal activity/secretion could be the basis for neuroendocrine anomalies that accompany the reproductive disturbances in the syndrome.
The GRASP proposal is based on data and concepts originating from the ERC Consolidator Grant REPRODAMH where we have shown, using a robust PCOS mouse model that we have generated (PAMH animals), the pivotal role of Anti-Müllerian Hormone (AMH) and GnRH in the onset of the reproductive and metabolic traits of PCOS. Importantly, we have demonstrated that intermittent delivery of low doses of a GnRH antagonist reversed neuroendocrine (LH and Testosterone, T) and reproductive (oestrous cycles and ovulation) PCOS traits in PAMH mice. In GRASP we have tested the hypothesis that a subtherapeutic dose of a GnRH antagonist, aimed at tempering LH secretion/pulsatility, can ameliorate both reproductive and metabolic PCOS traits in PAMH mice and we have performed a pilot clinical study in women with PCOS to explore the dose relationship of the effect of low GnRH antagonism in circulating hormones’ dynamics. Altogether, our data indicate that GnRH antagonism could pave the way towards a novel therapeutic strategy to ameliorate the reproductive and metabolic alterations associated with PCOS.
The international evidence-based guideline for the assessment and management of PCOS endorses the use of the Rotterdam diagnostic criteria, where a woman must have 2 out of the following 3 criteria for the diagnosis to be reached: sporadic or absent ovulation (oligo-anovulation, OA), biochemical or clinical evidence of hyperandrogenism (HA), and polycystic ovarian morphology (PCOM). HA is a common feature among women with PCOS, affecting nearly 80% of women diagnosed using the Rotterdam definition, which significantly contributes to the OA. The key neuroendocrine aberration in women with PCOS is increased luteinizing hormone (LH) pulse frequency, documented in 75 % of women with PCOS, regardless of their body mass index (BMI). This suggests an increase in activity of gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus. GnRH neurons are the master regulators of reproductive functions in mammals as they control fertility by driving the secretion of LH, and follicle-stimulating hormone (FSH) from the pituitary gland. These factors regulate the development and functions of the gonads in all vertebrates. In women with PCOS, the LH hyper-pulsatility contributes to increased ovarian thecal androgen secretion and failure of ovulation, constituting a pivotal pathogenic role in the syndrome. These evidences suggest that deregulation of GnRH neuronal activity/secretion could be the basis for neuroendocrine anomalies that accompany the reproductive disturbances in the syndrome.
The GRASP proposal is based on data and concepts originating from the ERC Consolidator Grant REPRODAMH where we have shown, using a robust PCOS mouse model that we have generated (PAMH animals), the pivotal role of Anti-Müllerian Hormone (AMH) and GnRH in the onset of the reproductive and metabolic traits of PCOS. Importantly, we have demonstrated that intermittent delivery of low doses of a GnRH antagonist reversed neuroendocrine (LH and Testosterone, T) and reproductive (oestrous cycles and ovulation) PCOS traits in PAMH mice. In GRASP we have tested the hypothesis that a subtherapeutic dose of a GnRH antagonist, aimed at tempering LH secretion/pulsatility, can ameliorate both reproductive and metabolic PCOS traits in PAMH mice and we have performed a pilot clinical study in women with PCOS to explore the dose relationship of the effect of low GnRH antagonism in circulating hormones’ dynamics. Altogether, our data indicate that GnRH antagonism could pave the way towards a novel therapeutic strategy to ameliorate the reproductive and metabolic alterations associated with PCOS.
The goal of the GRASP study was to establish proof-of-concept for this approach, paving the way for larger, long-term randomized trials to address the neuroendocrine dysfunction underlying the hormonal imbalances in PCOS and advance therapeutic innovation.
Preclinical Study (WP1)
In the first phase (WP1), we conducted a preclinical dose-response study to assess the efficacy of different doses of the GnRH antagonist Ganirelix in restoring normal LH pulse patterns in PAMH mice. The results indicated that sub-therapeutical doses of Ganirelix successfully normalized abnormal LH pulses, pulse amplitude, and testosterone levels in PCOS-like animals.
Clinical Pilot Study (WP2)
Building on the preclinical findings, we conducted a pilot clinical trial (WP2) using the same Ganirelix doses. Twenty women with PCOS, diagnosed according to the Rotterdam criteria, were recruited at Jeanne de Flandre Gynaecological Hospital of Lille (CHU-Lille) under the supervision of Prof. Sophie Catteau-Jonard. The trial concluded on February 12, 2025, with the last patient enrolled.
Participants (n=20) received a single subcutaneous injection of Ganirelix at two different doses. Blood samples were collected every 10 minutes, starting four hours before and continuing four hours after administration. Hormonal and biological assessments were performed at CHU-Lille.
Key Findings
Both Ganirelix doses successfully reduced LH levels and LH pulse peaks by approximately 30%, restoring them to normal physiological conditions. Additionally, we observed positive effects on secondary outcomes, including reductions in serum testosterone, androstenedione, and the LH/FSH ratio.
Next Steps
We are currently preparing the manuscript summarizing the findings from WP1 and WP2, with an anticipated submission by summer 2025.
Preclinical Study (WP1)
In the first phase (WP1), we conducted a preclinical dose-response study to assess the efficacy of different doses of the GnRH antagonist Ganirelix in restoring normal LH pulse patterns in PAMH mice. The results indicated that sub-therapeutical doses of Ganirelix successfully normalized abnormal LH pulses, pulse amplitude, and testosterone levels in PCOS-like animals.
Clinical Pilot Study (WP2)
Building on the preclinical findings, we conducted a pilot clinical trial (WP2) using the same Ganirelix doses. Twenty women with PCOS, diagnosed according to the Rotterdam criteria, were recruited at Jeanne de Flandre Gynaecological Hospital of Lille (CHU-Lille) under the supervision of Prof. Sophie Catteau-Jonard. The trial concluded on February 12, 2025, with the last patient enrolled.
Participants (n=20) received a single subcutaneous injection of Ganirelix at two different doses. Blood samples were collected every 10 minutes, starting four hours before and continuing four hours after administration. Hormonal and biological assessments were performed at CHU-Lille.
Key Findings
Both Ganirelix doses successfully reduced LH levels and LH pulse peaks by approximately 30%, restoring them to normal physiological conditions. Additionally, we observed positive effects on secondary outcomes, including reductions in serum testosterone, androstenedione, and the LH/FSH ratio.
Next Steps
We are currently preparing the manuscript summarizing the findings from WP1 and WP2, with an anticipated submission by summer 2025.
GRASP has the potential to be of high scientific impact, as it revealed new concepts in the fields of reproductive biology, PCOS and metabolism. The outcome is expected to be extremely important for the validation of a targeted therapy that would normalize the exacerbated LH pulsatility, hyperandrogenism, and according to our data, body weight and hyperinsulinemia. GRASP could thus have a quick and strong medical impact for millions of women suffering from this syndrome.
Based on the data stemming from our pilot clinical trial we are now searching for funding opportunities to perform a phase-2 clinical trial (cross-over double-blinded case-control study) using a long-term (6 months) GnRH antagonist treatment and assess the outcomes of this treatment on both fertility and metabolism in women affected by PCOS. This will allow the maturation and validation of our novel technology as well as the development of a business case towards the innovation’s future commercialization.
Our translation into drug discovery has a strong impact on society. From the science emerging from this ERC PoC, one of our previously filed patents (N° de publication: WO2018177746) has been accepted in US in February 2025 (US patent N°: US 12,208,130 B2).
In addition, in January 2025, I launched a start-up bio-incubation project, PCOS Well-being Innovations (PWI), under the support of Eurasanté, Région Nord, France and Inserm-Transfert. PWI is committed to advancing women's health by developing innovative treatments for PCOS, a reproductive and cardio-metabolic disorder affecting over 10% of women worldwide. Our approach focuses on repositioning GnRH antagonists as therapeutic agents while also exploring novel immunotherapy strategies.
For more information: https://www.clubster-nsl.com/annuaire-membres/pcos-well-being-innovations-pwi/(odnośnik otworzy się w nowym oknie)
Based on the data stemming from our pilot clinical trial we are now searching for funding opportunities to perform a phase-2 clinical trial (cross-over double-blinded case-control study) using a long-term (6 months) GnRH antagonist treatment and assess the outcomes of this treatment on both fertility and metabolism in women affected by PCOS. This will allow the maturation and validation of our novel technology as well as the development of a business case towards the innovation’s future commercialization.
Our translation into drug discovery has a strong impact on society. From the science emerging from this ERC PoC, one of our previously filed patents (N° de publication: WO2018177746) has been accepted in US in February 2025 (US patent N°: US 12,208,130 B2).
In addition, in January 2025, I launched a start-up bio-incubation project, PCOS Well-being Innovations (PWI), under the support of Eurasanté, Région Nord, France and Inserm-Transfert. PWI is committed to advancing women's health by developing innovative treatments for PCOS, a reproductive and cardio-metabolic disorder affecting over 10% of women worldwide. Our approach focuses on repositioning GnRH antagonists as therapeutic agents while also exploring novel immunotherapy strategies.
For more information: https://www.clubster-nsl.com/annuaire-membres/pcos-well-being-innovations-pwi/(odnośnik otworzy się w nowym oknie)