Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness in people over age 60 in the developed world. Progression of this disease results in the loss of the ability to perform activities highly correlated with quality of life. The disease process is not well understood. Treatments address only portions of the underlying mechanisms of the disease and there is no cure. The current standard of care is repeated intravitreal anti-vascular endothelial growth factor (anti-VEGF) pharmacologic treatment. However, only 34%-40% of patients gain clinically significant vision and maintain that gain over the course of one to two years. Currently non-responders are identified only after months of ineffective treatment. Our objective is to validate a panel of biomarkers that predict clinical non-responders to anti-VEGF monotherapy so that physicians can quickly identify patients who would benefit from alternative therapy rather than waiting for months to clinically demonstrate treatment failure before implementing these other therapeutic strategies. We have discovered the presence of cell receptors and their activated phosphorylated forms in the vitreous fluid of human eyes and that there are significant protein level differences between anti-VEGF treatment responders and non-responders. Ocular Proteomics, LLC (OPL)'s approach will be based on the use of reverse-phase protein microarray (RPPM) technology to accurately discriminate different disease states in at-risk patients. OPL is at the forefront of a small group that uses RPPM technology to investigate biomarkers for degenerative ocular diseases. Results will lead the way for this project to study the predictive potential of the vitreous proteome for retinal diseases, including wet AMD. Hypotheses 1) The baseline proteome of wet AMD patients is distinctive from that of healthy normals or patients with other types of eye diseases. 2) The baseline vitreous proteome of wet AMD non-responders to anti-VEGF therapy differs significantly from that of wet AMD responders. 3) Differences in the baseline proteome of responders and non-responders are likely to lie in proteins involved in the VEGF, angiogenesis, and/or inflammatory pathways.
The Specific Aims of the proposal are:
(Aim 1) use model of clinical response to form cohorts of vitreous samples for biomarker analysis, (Aim 2) profile candidate vitreous biomarkers using antibody microarrays, and (Aim 3) validate and quantify the biomarkers.
The proposed research will improve public health by improving the vision of patients with wet age-related macular degeneration at reduced costs. It will do this by producing a product that will allow retina physicians to perform a test that will determine how a patient will respond to a given treatment before starting the patient on this treatment. This will allow the doctor to choose the right treatment for the right patient at the right time, providing truly personalized medicine.
| Ecker, Stephanie M; Pfahler, Scott M; Hines, Joshua C et al. (2012) Sequential in-office vitreous aspirates demonstrate vitreous matrix metalloproteinase 9 levels correlate with the amount of subretinal fluid in eyes with wet age-related macular degeneration. Mol Vis 18:1658-67 |
