Drug Target Discovery for Age-Related Macular Degeneration (AMD) Through a Metabolomics Approach

Age-related macular degeneration (AMD) is the leading cause of vision loss in the western world among the elderly population. 90% of all vision loss due to AMD results from the exudative form, which is characterized by choroidal neovascularization (CNV). Age-related changes that induce pathologic CNV are incompletely understood and critical issues remain to be addressed. Metabolomics is defined as the comprehensive study of endogenous metabolites changes in various biological systems. This newly emerging “omic” science provides an unique opportunity to correlate variation of the metabolome with pathological occurrence or progression and/or to identify metabolites that are implicated in the disease1. To better understand the etiology of AMD, we decide to apply a NMR-based metabolomics approach on AMD patients and on a laser-induced murine choroidal neovascularization experimental model2.
For this purpose, sera from control and exudative AMD patients, induced and non-induced mice have been collected and the metabolic profiles of these samples were determined by NMR. After post-processing treatments, the different spectra were analyzed by statistical discriminant methodologies (PCA, ICA, PLS-DA, O-PLS-DA). This methodology allows discrimination between control and AMD patients and between control and CNV mice group. Moreover, the same discriminating spectral zones have been identified in human and mice model, leading to the emergence of different putative biomarkers. Among these markers, lactate emerges as a key metabolite in both settings. Mechanistically, lactate produced locally and by inflammatory cells plays a critical role in the onset of the inflammatory and angiogenic phases. In mice model of laser-induced CNV, normalization of circulating lactate by dichloroacetate a pyruvate dehydrogenase kinase (PDK) inhibitor decreases CNV development. PDK is therefore a putative target for AMD treatment.
Our data support the innovative concept of lactate as a parainflammation- and angio-metabolite associated to AMD and CNV progression. Moreover, control of blood lactate level via inhibition of PDK provides new options for the treatment of exudative AMD. This study demonstrates the ability of metabolomics for drug target discovery and opens new perspectives for AMD treatment and patient follow-up.