NMR-based metabolomics for new target discovery and personalized medicine : application to Age-related Macular Degeneration (AMD).

Nuclear Magnetic Resonance (NMR) is an indispensable analytical tool for research in the biomedical and pharmaceutical fields. More recently, NMR appeared as one of the major and more powerful technological platform for metabolomics approach. Metabolomics is a growing area of the “omics” sciences and is defined as the comprehensive identification and quantification of low-molecular weight metabolites in biological samples. It provides a unique and direct vision of the functional outcome of organism’s activities that could be correlated to pathologies and/or treatment administration. The links between metabolic changes, patient phenotype, physiological and/or pathological status and treatment are now well established and have opened a new area for the application of metabolomics in new target identification and in personalized medicine.
Age-related Macular Degeneration (AMD) is the leading causes of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form, which is characterized by choroidal neovascularization (CNV). Treatment is mainly based on regular intravitreal injection of anti-VEGF to stabilize CNV. Nevertheless, the comprehensive understanding of the pathogenesis and the evolution of this complex multi-factorial disease remain incomplete. Moreover, due to the long-term disease chronicity and to some resistance to treatment, a continuous follow-up of patients, a personalization of treatment and the discovery of new therapeutic approaches are mandatory. In order to study CNV occurrence and evolution and to get new and innovative insights into this pathology, we decided to apply a NMR-based metabolomics approach on both clinical and pre-clinical models (a murine laser-induced CNV model and patient’s cohorts). This approach led us to identify some metabolites linked to CNV developments in both human and murine samples. These molecules could be considered not only as markers of the pathology but also as putative target for a new treatment of AMD. Among those, lactate emerges as a key metabolite in both settings. Mechanistically, we demonstrated that lactate, initially produced in the eyes increases at the systemic level and play a critical role in the onset of the inflammatory and angiogenic phases. For this purpose, we use a combination of NMR measurements (both 1D and 2D) and molecular biology approaches. The control of the systemic concentration of lactate by PDHK inhibition or by LDH modulation decreases significantly CNV development.
Based on a metabolomics approach, our data support the innovative concept of lactate as a putative target for a new therapeutic approach of AMD as well as a useful marker for patient’s follow-up during treatment. We highlight also the utility and the efficacy of NMR for metabolomics and metabolites measurement in complex biological samples.