Inherited retinal degenerations are a major cause of blindness and are typically characterized by progressive death of the photoreceptors and retinal pigment epithelium (RPE). Although there are no currently approved treatments for inherited retinal degenerations, numerous therapeutic approaches are under development, including gene therapies. To maximize chances of success, developers of these therapies must know the natural sequence of degeneration in each disease, both to optimize the timing and retinal location of applied therapies as well as to enable evaluation of whether the therapies had an effect. Choroideremia (CHM) is an X-linked degeneration caused by mutations in the CHM gene that result in non- functional Rab Escort Protein 1 (REP-1). CHM mutations are known to cause progressive loss of the photoreceptors, RPE, and choriocapillaris, leading to blindness. To develop the best possible therapy for CHM, we must learn the answers to two fundamental questions: 1) What is the progression of cone functional loss in CHM on the cellular-scale? 2) Is this functional loss predicted by structural changes in the photoreceptor mosaic? Based on our preliminary data, we hypothesize in CHM that cones exhibit dysfunction prior to structural loss. To test this hypothesis, we will investigate cone function and its correlation with cone mosaic structure in CHM patients using a unique combination of state-of-the-art imaging modalities. We will make functional assessments of cone psychophysical sensitivity thresholds and stimulus-evoked reflectance responses by presenting visual stimuli through an adaptive optics scanning light ophthalmoscope (AOSLO). In addition, AOSLO has allowed non-invasive simultaneous observation of the cone inner segment (IS) and waveguiding outer segment (OS) mosaics, and we will use this technology to compare cone IS and OS structural abnormalities with residual cone function. There is currently no approved treatment for CHM. However, a Phase 1/2 clinical trial for CHM gene therapy is underway at the University of Pennsylvania. Gene therapy aims to treat the retina at the cellular level, and we propose to assess the safety and efficacy of the gene therapy intervention with that same cellular resolution. We hypothesize that gene therapy intervention for CHM will: a) be safe, b) slow or halt structural degeneration, and c) reverse photoreceptor dysfunction at retinal locations where cells are structurally intact but functionally compromised. To test these hypotheses, we will use our AO cellular imaging methods to assess photoreceptor structure and function in CHM patients treated with gene therapy. The information gained by this study will be applicable to all studies characterizing and treating CHM and more broadly applicable to treatment development and clinical trial design for blinding conditions beyond CHM, as well as for validating adaptive optics cellular scale outcome measures for use in future clinical trials.

Public Health Relevance

This project will utilize high resolution adaptive optics scanning light ophthalmoscopy to investigate the structure, function, and treatment of photoreceptors in human patients with Choroideremia, a blinding inherited retinal degeneration. This study will determine: 1) if cone function is tightly correlated with cellular structure, 2) the statistical limitations for using cellular biomarkers as markers for disease progression and 3) whether experimental gene therapy halts disease progression at the cellular level, all in Choroideremia. The information gained in this study will directly apply to all studies and therapies of Choroideremia, will aid future studies of inherited retinal diseases beyond Choroideremia, and will pave the way for adaptive optics technology to advance and accelerate gene, cell, and molecular therapies for blinding conditions.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Shen, Grace L
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University of Pennsylvania
Schools of Medicine
United States
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Morgan, Jessica I W; Vergilio, Grace K; Hsu, Jessica et al. (2018) The Reliability of Cone Density Measurements in the Presence of Rods. Transl Vis Sci Technol 7:21