Age-related macular degeneration (AMD) is the world’s most important age-related blinding disorder. The current proposal utilises epidemiological data describing clinical phenotype, molecular genetics, lifestyle, nutrition, and in-depth retinal imaging derived from existing longitudinal European epidemiological cohorts and biobanks to provide three major insights needed for long-lasting prevention and therapy for AMD: (a) the development of robust algorithms utilising genetic and non-genetic risk factors to identify personalised risks of developing advanced wet and dry AMD; (b) the identification of novel biomarkers for further stratification of disease risks. New insights from (a)+(b) will be used to elaborate preventive medical recommendations for highrisk subgroups of AMD patients; and (c) the identification of molecular drivers/biological pathways relevant for onset and progression of advanced AMD that will be used to identify and validate new therapeutic targets. Key deliverables are: 1. Determination of AMD frequency in Europe, and assessment of AMD risk for phenotypical, genetic, environmental, and biochemical risk factors and their interaction. (WP1-3) 2. Development of a web-based prediction model for personalised risk assessment of AMD based on integration of risk profiles derived from retinal imaging, molecular genetics, assessment of lifestyle, and biochemical testing. (WP4) 3. Modelling and functional characterisation of pathophysiological pathways identified from integrated analysis of current knowledge and the above risk profiles. (WP5) 4. Experimental testing and interpretation of pathophysiological consequences of risks at the molecular level. (WP6) 5. An extension and refinement of the prediction model (WP4) based on work in WP5 and WP6 to generate clinical guidelines for the medical management of high-risk subgroups of patients with AMD. (WP7) 6. Promotion and dissemination of newly gained knowledge towards AMD prevention and therapy development

Prevalent eye diseases, such as glaucoma, keratoconus, refractive errors, cataract, myopia and presbyopia, affect millions worldwide, and only in Europe represent over €20 billion annual cost to society. Current screening tools rely on morphological biomarkers based on corneal shape and optics, yet differences in biomechanical properties underlie and precede disease development (i.e. keratoconus, ectasia risk) or affect standard markers (i.e. intraocular pressure in glaucoma). IMCUSTOMEYE will develop new diagnostic paradigms for these vision-threatening conditions, with a direct impact on their treatment. We will deploy new compact, easy-to-use, label-free non-invasive imaging-based instrumentation for direct measurement of corneal biomechanical properties in patients. The technology is based on imaging concepts brought from other disciplines into ophthalmology and, for the first time, applied in patients in vivo. Dynamic corneal imaging based on air-puff stimulated Optical Coherence Tomography corneal deformation and acoustic stimulated phase sensitive and nanosensitive Optical Coherence Tomography corneal vibrography will be coupled to corneal mechanical models to estimate corneal elasticity and viscoelasticity parameters (isolated from other factors). Corneal biomechanical properties will be used as biomarkers for in-depth diagnosis of keratoconus and ectasia risk, and to provide accurate estimates of intraocular pressure in glaucoma diagnosis. Clinical validations in ophthalmology hospitals will demonstrate the diagnostic and treatment predictive potential of the customised optical and biomechanical eye models from patient-specific enabled by the new technology. IMCUSTOMEYE will contribute to more effective, customised treatment of eye diseases and to reinforce industrial leadership in the area of diagnostic imaging in ophthalmology.

Despite significant advances in the treatment and understanding of late stage age-related macular degeneration (AMD), it continues to be the main cause of irreversible severe visual loss in Europe and its prevalence and incidence will increase with current demographic trends. In order to reduce the significant burden of late stage AMD, novel interventions should aim at stopping or delaying progression from the preceding disease stage intermediate AMD (iAMD) to late stage AMD. As a prerequisite, validated clinical endpoints for iAMD are needed. These should be acceptable to regulatory agencies, health technology assessment (HTA) bodies, and payers. Currently such endpoints do not exist for iAMD clinical trials (CTs). In addition, there is good evidence indicating that patients with iAMD experience some impairment of visual function yet it is unknown to what extend this impacts the patients’ life nor can it be reliably measured and quantified. It is also unknown whether there are specific risk factors in the population of iAMD patients which identify those with more rapid progression to late stages of the disease. Therefore, to enable successful development of iAMD interventions validated functional, morphological and patient--reported endpoints for CTs, which are clinically meaningful and accepted by regulatory agencies, are required. In addition, functional decline in iAMD, as well as, specific risk factors for iAMD progression to late stage AMD need to be better characterized to inform and improve conduct of future iAMD CTs. Against this background, the major objective of MACUSTAR is to develop novel clinical endpoints for CTs with a regulatory and patient access intention in patients with iAMD. Additional objectives are to characterize visual impairment in iAMD and its progression, as well as, identify risk factors for progression. For clinical endpoint development, functional, structural and patient-reported outcome measures will be assessed with regards to