Associative mechanisms linking a defective minipuberty to the appearance of mental and nonmental disorders: infantile NO replenishment as a new therapeutic possibility

Informations projet

miniNO

N° de convention de subvention: 847941

DOI

10.3030/847941

Date de signature de la CE 5 Decembre 2019

Date de début 1 Janvier 2020

Date de fin 31 Octobre 2026

Financé au titre de

• SOCIETAL CHALLENGES - Health, demographic change and well-being

Coût total

€ 6 487 770,00

Contribution de l’UE

€ 6 487 770,00

Coordonné par

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 3 - miniNO (Associative mechanisms linking a defective minipuberty to the appearance of mental and nonmental disorders: infantile NO replenishment as a new therapeutic possibility)

Période du rapport: 2023-01-01 au 2024-06-30

Résumé du contexte et des objectifs généraux du projet

The hypothalamic-pituitary-gonadal (HPG) axis, a key hormonal system, is transiently activated during the early months of life in a phase known as minipuberty. This phase is crucial for the initial development of sexual organs, but then the axis remains inactive until puberty. Prematurely born individuals often experience altered minipuberty, which is a hallmark of preterm birth, yet the implications and mechanisms of this alteration are not fully understood. Research suggests that nitric oxide (NO), a molecule produced in the brain during infancy, may play a role in the events of minipuberty.
The EU-funded miniNO project seeks to explore the molecular links between NO deficiency, altered minipuberty, and the resulting multimorbidity, which includes both mental and physical disorders. This project brings together an interdisciplinary team of scientists and clinicians to investigate these associations. The goal is to validate the mechanisms causing multimorbidity in preterm births and to develop new diagnostic and preventive tools, such as biomarker screening tests and genetic factor identification. These advancements aim to enable personalized treatments and new therapeutic options, ultimately improving the quality of life for millions of individuals born prematurely and reducing the societal and financial burdens associated with their care.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The miniNO project has made significant progress in understanding the impacts of altered minipuberty on prematurely born individuals. Initially, a mouse model was created to simulate preterm birth, allowing researchers to study minipuberty in premature and Nos1-deficient mice. This research established a link between altered minipuberty and various mental and non-mental, physical health issues. Recently, the project has focused on testing nitric oxide (NO) treatment during minipuberty to address these developmental problems and improve neurodevelopment. In parallel, securing all necessary ethical approvals the clinical study was initiated. Fullterm infants or infants with alterations of minipuberty (prematurely born or with congenital hypogonadotropic hypogonadism), receiving or not NO supplementation therapy are currently being enrolled in the miniNO prospective cohort in the three collaborative hospitals, with blood samples collected for hormonal assessment as well as DNA and RNA sequencing. Protocols for assessing metabolic, cognitive and sensory functions in infants have been implemented. Socioeconomic factors are also being explored. In parallel, long-term studies involving pre-existing cohorts are underway, examining the effects of NO/sildenafil treatment on mental and physical health in cohorts followed up to age ten. Biomarker validation has progressed, with improved gene detection techniques generating data for numerous samples. Throughout the project, effective management and communication strategies have been employed, ensuring smooth operations and promoting the project's visibility through regular updates and activities. Overall, the miniNO project is advancing our understanding of minipuberty's role in the health of prematurely born individuals and developing potential interventions to improve their long-term outcomes.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The miniNO project is advancing the understanding of the biological mechanisms underlying minipuberty and its impact on brain development and human physiology. This research explores the potential of nitric oxide (NO) therapy as a preventive treatment for neurodevelopmental dysfunctions in high-risk populations, such as premature infants or infants with altered minipuberty due to genetic imbalances. By analyzing the long-term effects of NO/sildenafil treatment, the project aims to assess the safety and benefits of these therapies in preventing mental and non-mental disorders. Additionally, the project investigates the genetic, epigenetic, and socio-economic factors contributing to the comorbidities associated with prematurity, identifying potential biomarkers for early diagnosis and treatment. By enhancing our understanding of early human neurodevelopment (through our preclinical models and the clinical cohorts) miniNO has broader societal implications aiming to mitigate the risks associated with prematurity and inform public health strategies.Thanks to the advancement of the project, we expect that miniNO will be able to generate new diagnostic kits for clinical use, which could significantly improve the management of preterm infants at risk of developmental disorders. The project holds promise for substantial socio-economic impacts by potentially reducing healthcare costs and improving the quality of life for affected individuals.

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