OCT-based functional biomarkers for degenerative diseases of the photoreceptor-RPE-choroid neurovascular unit Abstract: Important diseases of the photoreceptor-RPE-choroid neurovascular unit include age-related macular degeneration (AMD), retinitis pigmentosa (RP), and other inherited retinal degenerations (IRDs). The number of people with AMD worldwide is nearly 200 million, and expected to approach 300 million over the next twenty years, while IRDs affect more than 5 million more. AMD is the leading cause of blindness in the industrialized world, and also the leading cause of blindness among people over the age of 60. Standard treatments exist for neither the more prevalent dry form of AMD nor IRDs, and key obstacles to discovering them are 1) limited understanding of the pathogenic steps leading to vision loss; and 2) lack of biomarkers for disease progression and recovery. In recent years our team has pioneered the emerging field of optoretinography (ORG) using adaptive optics (AO) and OCT. The ORG is an all-optical, noninvasive, objective measure of neural function in the retina, and has the potential to yield new functional biomarkers of retinal disease. Due to the cost and complexity of AO-OCT imaging systems and their subsequent scarcity, ORG measurements have been made only in small numbers of volunteers, mostly without retinal disease. We propose to develop a next-generation, proto-clinical ORG system and characterize its sensitivity, dynamic range, and spatial resolution. First, we will test a number of modifications to the protocols for imaging and signal processing, with a focus on improving the clinical utility of the method. Second, in healthy subjects and several patient populations we will measure ORG responses, along with other OCT-based measurements such as structural OCT imaging and OCTA. The patient populations to be studied are: 1) IRD patients including those with Stargardt’s disease and retinitis pigmentosa; 2) intermediate AMD patients with drusen, subretinal drusenoid deposits, and/or hyperreflective foci; and 3) late AMD patients with regions of geographic atrophy. The motivations for these patient populations are 1) to test hypotheses about the mechanisms underlying the ORG response, and 2) to demonstrate the ORG’s capacity to detect and quantify disease-related dysfunction. The proposed work will result in 1) a clinically useful ORG platform (also capable of structural and angiographic imaging), and 2) new knowledge that will permit us to design ORG- and OCT-based biomarkers for retinal disease that relate to mechanisms of action and have characterized sensitivity to photoreceptor dysfunction.