Lipid Regulators of Choroidal Neovascularization

In “wet,” or neovascular, age-related macular degeneration (AMD), abnormal blood vessels grow from beneath the retina that are immature in nature and leak fluid below or within the retina. This can lead to a rapid loss of eyesight. Emerging data implicate lipids derived from the cytochrome P450 pathway, which act as potent regulators of angiogenesis. Thus, it is of great clinical interest to elucidate the mechanisms by which these lipid mediators facilitate disease development and/or regression. Our proposal has clear potential to lead to new therapeutic molecules, targets, and strategies for specifically inhibiting neovascular AMD, a leading cause of blindness in the elderly which, if left untreated, rapidly leads to substantial vision loss.

The goal of this proposal is to define the mechanism of action for potent bioactive lipid metabolites, derived from the cytochrome P450 (CYP) pathway, for their ability to suppress neovascular age-related macular degeneration (AMD).

The study is designed to characterize the efficacy of dietary intake of omega-3 long-chain polyunsaturated fatty acids (ω-3 LCPUFAs) and their regulation of CYP metabolites in the primary mouse model of choroidal neovascularization (CNV).

The major dietary and structural ω-3 LCPUFAs of the retina are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are thought to modulate processes implicated in AMD pathogenesis. Our preliminary results support this hypothesis; thus, we are assessing the role of these diets along with specific modulators of the CYP lipid biosynthetic pathway for their potential to regulate neovascular disease (Aim I). To determine which CYP metabolites are protective or deleterious to disease progression, we are quantifying retinal and serum levels of the specific CYP-derived lipid metabolites during disease by liquid chromatography-mass spectrometry (LC MS) (Aim I). Given the role of the immune system in neovascular ocular disease, and the ability of these biometabolites to modulate immune cell function, we measure a panel of key genes involved in angiogenesis, lipid metabolism, and inflammation in these mice as well as their ability to modulate specific immune cell subtypes in the CNV lesion (Aim I). Lastly, specifically, modulated lipid metabolites or specific inhibitors of the CYP pathway are assessed for therapeutic potential in CNV (Aim II).

To our knowledge, this proposal is the first attempt to identify and define the actions of specific CYP metabolites in neovascular AMD. We hope to clearly identify specific CYP-derived lipid biometabolites involved in the protective actions of the ω-3s, determine their ability to locally regulate the angiogenic and inflammatory CNV lesion microenvironment, and assess their potential as a possible therapeutic for neovascular AMD disease progression. We feel the potential impact of this study may be relevant not only to AMD but also to other conditions that involve angiogenesis and inflammation, such as diabetic retinopathy, atherosclerosis, and cancer for the following reasons: 1) high presence of these lipids within tissues; 2) the preference of CYPs for DHA and EPA processing; and 3) the proven regulation of angiogenesis and inflammation by these metabolites in vascular tissue.

The current standard of care for patients with CNV involves inhibiting the proangiogenic and permeability-regulating molecule known as vascular endothelial growth factor-A (VEGF). However, in patients treated with VEGF antagonists, substantial vision improvement occurs in only one-third, and one-sixth of treated patients still progress to legal blindness. Thus, there is an urgent need for safe nutritional or pharmacological interventions for the early treatment of exudative AMD. We anticipate that our work will clearly outline specific CYP-derived lipid biometabolites involved in the protective actions of the ω-3 LCPUFAs, determine their mode of action, and confirm their potential as a possible therapeutic for neovascular AMD disease progression.