Cysteinyl leukotrienes (CysLTs) are potent lipid mediators of inflammation. CysLT1 and 2 receptors are widely expressed e.g. lungs, colorectum, heart, brain & eye; and CysLT1 antagonists are prescribed to treat airway inflammation. Excitingly, CysLT signalling was recently discovered to regulate the biology of vascular, neuronal and cancer cells underpinning its untapped therapeutic potential in other diseases. CRYSTAL3 interconnects unique and diverse researchers to create a multidisciplinary team sharing expertise and research capacities. The contribution of CysLT signalling to disease is divulged; its therapeutic potential unlocked and new services & products commercialised. This is delivered by staff exchanges to jointly research Ocular & Central Nervous System (CNS), Cardiovascular system (CV) and Cancer diseases. The R&I goal of CRYSTAL3 is to reduce human disease burden by enhancing EU capability and knowledge-sharing in research and commercialisation. This is achieved through advanced international co-operation between 5 academic and 5 non-academic partners, in 7 countries. The focus is on innovative research into the CysLT signalling pathway in human diseases related to the Ocular-CNS, & CV systems and Cancer (OCCC). The 3 overall objectives of CRYSTAL3 are: A) Combine resources to discover novel pathological mechanisms linking cysteinyl leukotriene signalling to ocular, central nervous system, cardiovascular disease and cancer (OCCC). B) Unite partner capacities to uncover the therapeutic potential of cysteinyl leukotriene signalling in ocular, central nervous system, cardiovascular disease and cancer (OCCC). C) Commercialise products and services co-developed within CRYSTAL3 The CRYSTAL3 consortium tackles these challenges by promoting cross-sector, inter-European R&I staff exchanges among participants with expertise in OCCC disease, computational drug discovery, genetic engineering, pre-clinical disease models, marketing and commercialisation.

Retinopathies constitute an extreme societal and socioeconomic burden that is expected to increase with an aging population and the increased prevalence of diabetes. These diseases, including age-related macular degeneration and proliferative diabetic retinopathy share neovascularization as a common etiology involving the pathological growth of retinal capillaries leading to blindness if left untreated. Current treatment modalities involve specialized injections into the eye that require not only outpatient visits to specialized treatment centers but are also associated with significant adverse effects. Orally bioavailable medications could revolutionize the treatment of retinopathies, by reducing adverse effects, sustaining vision, lowering the direct and indirect financial burden associated with these diseases, and increasing access to healthcare. Inspired by this idea, we have developed an approach that can be exploited to target essentially any therapeutic molecule to the eye. Our novel strategy of drug targeting will not only enrich the modified molecules in retinal tissue but will also reduce the therapeutic oral dose compared to existing anti-angiogenic therapy in cancer thereby increasing the safety of the treatment. This is achieved by absorbing a minute amount of the chemically and biologically stable molecules resulting in an extremely low plasma concentration and relying on a biological mechanism in the eye to activate the molecules to tether them to retinal target receptors and thereby extracting them from the blood. In the present application, we propose to demonstrate proof-of-concept of this strategy by modifying inhibitors of the vascular endothelial growth factor receptor (VEGFR). VEGFR is an endothelial receptor tyrosine kinase that is a key mediator of angiogenesis and an established drug target for the treatment of retinopathies. Our approach will elicit a paradigm shift in how we design future drug delivery strategies to the retina.

Diseases of the posterior segment of the eye are increasing considerably, partly due to an ageing population (almost 20% of the population of Europe now over 65). Despite accounting for approximately 55% of ocular conditions, only 5% of ocular product sales target the posterior segment due to the technical difficulties in developing safe, effective and easy-to-use formulations. Age-related Macular Degeneration and Diabetic retinopathy are some of the main cause of blindness and severe impairment of vision in patients. These diseases represent a considerable burden on patients and healthcare systems throughout the world. ORBITAL has the primary objective of recruiting excellent early stage researchers (ESRs) and developing the next generation of research leaders and drivers. There is a clear unmet clinical need for efficient, safe, non-invasive and patient-friendly strategies for the treatment of prevalent diseases of the posterior segment of the eye. With a necessary collaborative network of European and global experts, from academic, clinical and industrial sectors, ESRs will be exposed to an integrated and complementary network of expertise in materials science, nanotechnology, animal modeling, enhanced in-vitro testing, analytical chemistry and drug discovery. ORBITAL will build an intersectoral consortium with extensive experience in generating innovative technologies and training new researchers. ESRs will be exposed to a broad scientific landscape of complementary disciplines. With the combined skills and knowledge of the consortium, ESRs will be provided with the network, skills and knowledge to develop their careers while the extensive mobility of researchers will lead to increased knowledge transfer and collaborative research