Better drugs are one of the most efficient and sustainable ways to improve health care, a key strategic orientation in Horizon Europe. New drug modalities such as macrocycles are expected to be a key enabling technology for this strategic perspective. The goal of MC4DD is to train the next generation of European medicinal chemists in a multidisciplinary environment to promote European drug discovery competitiveness, directly by advancing knowhow on macrocycles and long-term via the skills carried on by the researchers trained in the doctoral network.

Alzheimer’s disease (AD) is an age-related chronic neurodegenerative disease with four main pathological changes in the brain: amyloid plaques, fibrillary tau tangles, inflammation and neuronal loss. Phagocytes around amyloid plaques in late onset AD (LOAD) may be neurotoxic but have limited motility and phagocytic activity, suggesting a dysfunctional activation. These phagocytes express the innate immune receptor TREM2 and CD33. Variants of both genes have been linked to LOAD. The main objectives of PHAGO are to find means of modulating microglia/macrophage activation via TREM2, CD33 and related signalling pathways, and determine the effects of such modulation on microglia/macrophage function, amyloid-β and neurodegeneration, in order to find a treatment for AD. PHAGO will deliver well characterized tools and knowledge through which to manipulate AD risk and provide targets and markers ready to progress to drug development. PHAGO will realise this goal by comprehensively attacking the problem simultaneously at multiple levels, including the molecular structures of the receptors, receptor ligand interactions, ectodomain function in vitro and in vivo, characterisation of receptor processing, modification and signalling, receptor-regulated signalling pathways, gene expression and phagocyte function in cells and animals, comprehensive analysis of receptor knock-in and knock-out models crossed to two different animal models of AD, and identification of receptor-related biomarkers in AD patients. Innovative approaches of PHAGO will include identification of new AD-risk genes using a TREM2 co-expression network approach, brain imaging of AD patients with TREM2 and CD33 variants, and generation of patient iPSC-derived microglia/macrophages to comprehensively phenotype gene variants. The project will also generate tools, such as ligands, reporter cells and optimised assays, suitable for further development of treatments targeting TREM2 and/or CD33 in AD.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, with a multifactorial aetiology, heterogeneous manifestation of motor and non-motor symptoms, and no cure. PD is often missed or misdiagnosed, as early symptoms are subtle and common with other diseases, allowing for considerable damage to occur before treatment. Moreover, selecting the optimal medication regimen is usually a lengthy, “trial and error” process, leading to critical, costly non-adherence. Following a trustworthy and inclusive approach to AI development and based on multidisciplinary expertise and broad stakeholder engagement, AI-PROGNOSIS aims to advance PD diagnosis and care by: 1) developing novel, predictive AI models for personalised PD risk assessment and prognosis (in terms of time to higher disability transition and response to medication) based on multi-source patient records and databases, including in-depth health, phenotypic and genetic data, 2) implementing a system of biomarkers informing the AI models by tracking key risk/progression markers in daily living, and ultimately 3) translating the models and digital biomarkers into a validated, privacy-aware AI-driven toolkit, supporting healthcare professionals (HCPs) in disease screening, monitoring and treatment optimization via quantitative, explainable evidence, and empowering individuals with/without PD with tailored insights for informed health management.

1.Our consortium has broad, deep experience of drug development and imaging biomarker (IB) validation. We are internationally recognized experts in transporter biology, animal models of lung injury, toxicology, DCEMRI, compartmental modeling, 1H&129Xe lung MR, and labeling of biologicals with PET and fluorescence tags, together with physicians who care for relevant patients. We have an outstanding record of translating IBs: (a) into animals, (b) into man, (c) into tools which drug developers use with confidence in clinical trials of investigational agents, (d) into regulatory drug development and healthcare. We will develop and validate the required IBs and make them commercially available. 2.Building on our previous work with gadoxetate DCEMRI IBs we will develop and standardise, define sensitivity and specificity in rats, and show valid and comparable data multicentre in human volunteers and patients. 3.We believe the search for IBs of Drug Induced Interstitial Lung Disease (DIILD) should start in DIILD patients. Cancer and rheumatology patients receiving, in their standard care, drugs with DIILD liability, and whose physicians withdraw the drug due to suspected DIILD, will be imaged when symptomatic and followed up. From this we will derive IBs of DIILD which predict outcome. We will also develop IBs from 1H/129Xe MRI and PET to further characterise DIILD, and will back-translate and validate all these IBs in rat models. 4.To better assess biodistribution of biologics, we will thoroughly characterise two well-chosen exemplars in rats, pigs and humans: an antibody biologic and a peptide biologic. We will use 89Zr, 18F and 68Ga PET, fluorescence and MALDI imaging. 5.We will follow an imaging biomarker roadmap to establish (a) that the IBs can be deployed robustly in whatever centre they are needed, (b) the relationship of the IB to underlying biology, (c) how well the IB forecasts clinical outcome, and make appropriate arrangements for dissemination.