Clear evidence supports associations between endocrine disrupting chemical (EDC) exposure and impaired neurodevelopment. Yet, current hazard assessment of EDCs does not address developmental neurotoxicity. This is due to lack of scientific knowledge on how endocrine disruption is linked to developmental neurotoxicity (DNT). Thus there is an urgent need for novel testing and screening tools to address ED-induced DNT, based on new scientific knowledge. This calls for rapid advances in basic research as well as in the development of screening and testing tools close to the end-users. ENDpoiNTs will address this need by i) integrating advanced expertise in the EDC and DNT fields, two so far rather independent toxicology communities, and ii) continuous interaction with European and international key stakeholders. By combining state-of-the-art in silico and in vitro tools, innovative experimental designs and technologies, and advanced biostatistics on human epidemiological and biomonitoring data, ENDpoiNTs will 1) Generate the necessary scientific insights on the correlative and causal links between endocrine disruption and DNT; 2) Develop predictive in silico tools for chemical screening using machine learning and combination of evidence; 3) Develop and validate in vitro tools for chemical screening and testing that address sex- and species differences; 4) Develop novel molecular endpoints for existing animal-based test guidelines by integrating in vitro, in vivo, and human omics data with behavioural outcomes; 5) Ensure human relevance by linking experimental and epidemiological evidence; 6) Develop an integrated testing approach based on the developed in silico, in vitro, and in vivo assays and molecular markers; 7) Ensure regulatory relevance by developing strategies for implementation of these tools and endpoints into regulatory frameworks. In this way, ENDpoiNTs will meet the scientific, regulatory, and societal needs for improved hazard and risk assessment of EDCs

Genetic skeletal diseases (GSDs) are an extremely diverse and complex group of rare genetic diseases that affect the development the skeleton. There are more than 450 unique and well-characterised phenotypes that range in severity from relatively mild to severe and lethal forms. Although individually rare, as a group of related genetic skeletal diseases, GSDs have an overall prevalence of at least 1 per 4,000 children, which extrapolates to a minimum of 225,000 people in the 27 member states and candidate countries of the EU. This burden in pain and disability leads to poor quality of life and high healthcare costs. Metaphyseal chondrodysplasia, type Schmid (MCDS) results from mutations in collagen X and affects <1/100,000 of the population. Mutant collagen X molecules miss-fold during synthesis and are retained within the endoplasmic reticulum (ER) of hypertrophic chondrocytes, thereby causing ER stress. Our extensive pre-clinical studies have shown that carbamazepine (CBZ) can alleviate ER stress caused by the expression of mutant collagen X and restore bone growth in a validated mouse model of MCDS. CBZ is an FDA approved drug used for the treatment of epilepsy and bipolar disorder and received orphan drug designation by the European Commission for the treatment of MCDS in September 2016. MCDS-Therapy was originally proposed as a 5-year collaborative project comprising world-renown clinical centres and SMEs to advance the repurposing of CBZ for MCDS (up to the Marketing Authorization Application dossier) through a multicentre and multinational (EU & AUS) clinical trial (Phase1, Phase2/3). MCDS-Therapy also encompasses biomarker development and health economics assessment studies to deliver, evidence to inform potential further studies of an innovative and affordable (CBZ already exists in a generic form) repurposed therapy for MCDS along with the diagnosis/prognosis tools to personalise the treatment strategy. The original proposal was for completion of this by 2022 however delays associated with the COVID pandemic have resulted in a need to extend the project with completion now forecast by May 2024.