As therapeutic interventions for retinal diseases are being rapidly developed, monitoring these interventions during clinical trials and understanding their natural history has taken on increased importance. The human retina is easily accessible through the use of a variety of imaging tools, such as spectral domain optical coherence tomography (SDOCT) and adaptive optics scanning light ophthalmoscopy (AOSLO). One inherited retinal disease with future and ongoing clinical trials is achromatopsia (ACHM), which affects 1 in 30,000 people. ACHM is a congenital retinal disease associated with absent or severely reduced cone function, while rods are thought to be unaffected. Currently, mutations in CNGA3 and CNGB3 account for approximately 70% of ACHM case. With the implementation of a recent imaging tool, split-detector AOSLO, visualizing remnant cone structure in the ACHM fovea is now possible. Since in ACHM cones are still present in the retina despite not having function, ACHM would be a good model to study the hyperreflective outer retinal bands on SDOCT. However, the rod and cone photoreceptor contribution to SDOCT signal and the symmetry of foveal cones structure in ACHM are yet to be elucidated. These knowledge gaps represent critical barriers to the understanding of clinical images needed for the advancement of therapeutic interventions for ACHM and other inherited retinal diseases. Therefore, the following aims are proposed:
Aim 1 : Assess variability of foveal cone structure in ACHM;
Aim 2 : Evaluate cone and rod contributions to SDOCT intensity as biomarkers for photoreceptor structure.
For aim 1, characterizing foveal cone structure in CNGA3- and CNGB3-associated ACHM will utilize SDOCT to measure outer nuclear layer thickness and split-detector AOSLO to measure peak cone density. This work should result in an improved understanding of the natural history and variability of foveal cone structure in ACHM. The degree of remaining cone structure could aid in patient selection for future clinical trials.
For aim 2, SDOCT intensity will be measured using directional OCT and photoreceptor structure using AOSLO. This work should result in a model to predict the intensity of bands 2 and 3 as a surrogate marker for the degree of photoreceptor structure. These results will aid in interpretation of clinical images in patients with a range of inherited retinal diseases.
The aims proposed here are significant because they advance our understanding of photoreceptor structure in ACHM. More broadly the methods developed here will aid in the interpretation of clinical images of photoreceptor degeneration and therapeutic interventions, and provide useful evidence toward the interpretation of the hyperreflective outer retinal bands on SDOCT.
With the rapid development of therapeutic interventions for retinal diseases, monitoring these interventions during clinical trials and understanding their natural history has taken on increased importance. This fellowship proposal aims to assess variability of foveal cone structure in achromatopsia and evaluate photoreceptor contributions to spectral domain optical coherence tomography intensity as biomarkers for photoreceptor structure. These studies provide an excellent postdoctoral training experience in translational research and will improve our understanding of photoreceptor structure in achromatopsia and interpretation of clinical images of photoreceptor degeneration and therapeutic interventions.
