Development of a novel, noninvasive, sensitive measure of retinal dysfunction

PROJECT SUMMARY/ABSTRACT Retinal diseases such as diabetic retinopathy affect >100 million world-wide, and detection of retinal dysfunction is often delayed due to the paucity of scalable early diagnostics. This predicament is problematic, as patient outcomes are improved with early detection. Early diagnosis of diabetic retinopathy before patients develop visual symptoms offers opportunities to treat hyperglycemia and prevent vision loss. While diabetic retinopathy preferentially affects the inner retina as determined by electroretinogram (ERG), other diseases such as retinitis pigmentosa (RP) affect the photoreceptors in the outer retina. Clinically, photoreceptor degeneration can advance without reducing visual acuity below normal limits until the majority of foveal cones are lost. This shortcoming has been validated by adaptive optics scanning laser ophthalmoscopy (AOSLO) to compare cone densities with the results of conventional localized measures of visual function, including visual acuity and macular sensitivity in patients with RP. While ERG and AOSLO are sensitive enough to detect the earliest signs of diabetic retinopathy and RP, respectively, they are not widely available as standard of care, and identifying additional sensitive and simple tests would facilitate earlier diagnosis and also accelerate the progress of clinical trials of new treatments, where more precise outcome measures are required to evaluate safety and efficacy. Thus, there is a critical need for the invention of new highly sensitive, scalable diagnostics for retinal dysfunction. This proposal aims to develop a scalable, sensitive diagnostic method for clinical measurement of retinal dysfunction with improved sensitivity over the current standard of care. The motivation for this pursuit comes from our preliminary data showing that graded cone loss can be detected in mice by measuring a highly- conserved, visually-evoked compensatory behavior known as the optokinetic reflex (OKR). The goal is to expand this methodology to the clinic for the detection and monitoring of localized cone and inner retinal function. To achieve this goal, we will develop OKR-inducing stimuli that are optimized to probe graded macular function in humans and compare OKR responses with structural measures of cones using AOSLO and functional measures using ERG in control subjects and in (Aim 1) RP patients and (Aim 2) diabetic patients. Our central hypothesis is that OKR gain (i.e., eye movement relative to stimulus movement) will be modulated with photoreceptor density, regularity, and inner retinal function. The rationale for developing an approach to interrogate cone densities and inner retinal function includes that (1) such a test would provide more sensitive measures of cone survival compared to visual acuity, which is the current standard, and (2) early intervention could preserve critical elements of human vision, including high-acuity foveal vision. Completion of this project would yield critical tools for improving diagnosis of retinal dysfunction and the monitoring of disease progression. Such advances would not only tangibly deliver improved patient outcome measures, but also open the opportunity for early intervention via a multitude of developing therapeutics.