NMR-Based metabolomics study of Age-related Macular Degeneration (AMD): from pre-clinic model to new target discovery

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). Treatments are mainly based on regular intravitreal injection of anti-VEGF to stabilize CNV. Nevertheless, despite such important advances, some clinical issues remain to be addressed. Among those, the personalization of the therapeutic strategies and the discovery of new therapeutic approach are essential. In order to study CNV occurrence and evolution, we decided to apply a NMR-based metabolomics approach on a murine laser-induced CNV model and on patient’s cohorts.
Metabolomics led us to identify some metabolites linked to CNV developments in both human and murine samples. These metabolites 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 plays a critical role in the onset of the inflammatory and angiogenic phases. The control of its systemic concentration 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 parainflammation- and angio-metabolite associated to AMD and CNV progression. It appears as a putative target for a new therapeutic approach as well as a useful marker for patient’s follow-up during treatment.