The main objective of ERROR is to develop a new software tool, which will offer to the clinician the possibility to assess alternative imaging and therapeutic protocols, in real time, in silico, in order to minimize patient dose, while maintaining image quality of therapeutic effect. This tool will be designed, implemented and evaluated with specific focus on pediatric patients, since this is a rather sensitive target group, where dose considerations are high and no standard protocols and solutions exist. The project will exploit the new generation of computational anthropomorphic phantoms, in combination with well validated Monte Carlo simulations and Machine Learning Tools. In this way, it is envisaged that advanced, yet mature technologies will be integrated, to provide a novel tool, which can lead to a final product. The ERROR project brings together a multidisciplinary consortium of specialists in different areas of medical physics, biomedical engineering, physicians and computer engineers, who will join forces in order to design, implement and clinically assess a novel software tools, which initial focus in the optimization of diagnostic and therapeutic protocols for pediatric exams. Two new SMEs will provide their expertise, as well as investigate the ways to exploit project outcome. A well planned exchange program among academic and industrial partners will facilitate knowledge sharing, maximize collaborative work and finally achievement of project objectives. The consortium, being aware of the scientific and social importance of pediatric clinical applications, has planned a series of dissemination and training activities, aiming at making project knowledge and outcomes available to the scientific community and society.

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition affecting over five million people in the European Union. The combination of core symptoms (deficits in social-communication and repetitive and restricted behaviours and interests) and common comorbidities (e.g. epilepsy and depression) significantly reduces the quality of life and life-span of affected individuals. Currently there are no effective drug treatments for the core symptoms. Key factors that have hampered progress include; 1) limited understanding of the underlying pathophysiolog(ies); 2) lack of successful translation from animal models to humans; 3) testing of drugs with specific actions in biologically heterogeneous populations; 4) limited expertise of many European ASD centres in running large-scale clinical trials; and 5) trial designs (e.g. placebo effects). Our vision, therefore, is to apply a precision medicine approach to ASD and improve patient outcomes by tailoring treatments to a patient’s biological profile. Our efforts will build on the achievements of 5 other IMI initiatives, 4 Horizon 2020 networks, and 6 SMEs for the first time to; 1) align global resources to validate and qualify stratification biomarkers from infancy to adulthood; 2) develop objective outcome measures that can be used in trials; 3) create a European-wide clinical trials network that reliably carries out studies able to support filings to the EMA/FDA; 4) carry out better targeted clinical trials linked to other international efforts – including quick wins or “fast fails” of ineffective agents; 5) translate molecular mechanisms and drug effects between preclinical models and particular subtypes of ASD. Together we will bring Europe to the forefront of clinical research in ASD. Also we will provide a sustainable legacy that is accessible by others across the world, attracts industry into ASD, and helps transform healthcare.

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.

PROBLEM: Medical-related-osteonecrosis of jaw (MRONJ) is a rare, but severe side effect of bone-targeting agents (BTAs), such as bisphosphonates. These agents are prescribed to survivors of breast cancer where they reduce the risk of secondary bone cancer. Unfortunately some people develop MRONJ, where progressive destruction of the jawbone leads to frequent infections, inability to eat and risk of malnutrition. MRONJ treatment focuses on controlling infection, pain and bone death through long courses of antimicrobial agents, contributing to development of antimicrobial resistance. Currently, ~12,000 people across Europe and the UK suffer from MRONJ. As people survive cancer longer, the number of cases is increasing. We urgently need a new prevention and treatment strategy for MRONJ. INNOVATION: GreenNanoBone will develop and validate sustainable, biocompatible, bioactive and antimicrobial 4D material to promote bone and tissue regeneration in a new strategy to prevent and treat MRONJ. The material will be injectable or printable as a scaffold for use in non-invasive surgical procedures. We will use AI to refine the properties of our plant-derived materials, test them using pre-clinical models, and ensure that they can be manufactured to medical standards. IMPACT: We address a clinical need and will reveal the pathophysiological mechanism of MRONJ in readiness for Phase I clinical trials (TLR-6) by the end of the project. In the longer term GreenNanoBone will dramatically increase quality of life for MRONJ patients and open up exciting possibilities for treating complex fractures and other skeletal conditions. We will develop a sustainable manufacturing process using recycling and clean raw material from a food (potato) waste side stream. The technology will enable production scale-up using climate-neutral methods. Our work will support European industries to undergo a Green Transformation and develop new markets, products, and services, boosting competitiveness.