Structure-Function Relationships at a Cellular Level in Choroideremia using Adaptive Optics Scanning Light Ophthalmoscopy

Awardee: Jessica I. W. Morgan

Institution: University of Pennsylvania

Grant Amount: $61,273.00

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Choroideremia (CHM) is an X-linked retinal degeneration affecting approximately 1 in 50,000 worldwide. Patients with CHM experience progressive degeneration of photoreceptors, retinal pigment epithelium (RPE) and choroid resulting in night blindness, loss of visual fields, and ultimately loss of central acuity. On retinal images, diffuse atrophy of the choriocapillaris and RPE can often be observed in peripheral areas, which gradually enlarges towards the central retina as the disease progresses. Subtle changes in retinal structure and function within the centrally retained retinal island often remain undetected using standard clinical evaluations. In addition, there is no clinical method to assess the structure or function of individual photoreceptors though gene therapy approaches attempt to restore function to individual cells that remain structurally preserved. The need for more sensitive biomarkers of photoreceptor structure and function is clear. The overall goal of this project is to understand photoreceptor structure and function at the cellular scale within the centrally remaining photoreceptor mosaic in CHM. To do this, our lab utilizes adaptive optics scanning light ophthalmoscopy (AOSLO) which allows non-invasive, single-cell level visualization of the human retina. We have further equipped our AOSLO with tools for measuring photoreceptor function including (1) optoretinography (ORG) and (2) AO-microperimetry. ORG measures an optical signal that arises from the photoreceptors when presented with visual stimuli, while AO-microperimetry enables measurements of visual thresholds for small stimuli, including for single cones. None of these measurements is achievable using conventional clinical devices. Using the AOSLO, we have previously observed patches of hyper- and hypo-reflective cones within the centrally preserved retina as a common CHM retinal feature. This project aims to study the relationship between this structural phenotype and functional measurements made through ORG and AO-microperimetry. The outcome of this project will help us understand the correlation of retinal function with local variations in structure throughout the photoreceptor mosaic, which will ultimately be helpful for monitoring disease progression and assessing treatment efficacy. Our long-term goal is to provide the field with novel, sensitive and non-invasive biomarkers for assessing individual cone function in CHM to aid in disease assessment and treatment design.