Predicting gene therapy success: Developing criteria from AOSLO imaging

Abstract

Objective: Several clinical trials for inherited photoreceptor disorders are set to begin, and one area of interest is the development of metrics to predict whether there will be a successful outcome. With the advent of adaptive optics imaging, it is now possible to directly characterize photoreceptor structure, though analytical tools to quantify the therapeutic potential from such images are lacking. Here we present several possible criteria to assess residual photoreceptor structure in subjects with inherited cone degenerations.

Methods: Two adaptive optics scanning light ophthalmoscopes (AOSLO), at the Medical College of Wisconsin and University College London were used to image the photoreceptor mosaic of subjects with genetically confirmed photoreceptor disorders as well as normal controls. Images were obtained, processed and montaged using previously described methods.¹ For all subjects, the average cone inner segment diameter was measured along two axes of the cell. Residual cone structure was graded as either waveguiding (bright) or non-waveguiding (dark). Reflectance profiles for waveguiding cone were also graded.

Results: Residual photoreceptor structure was abnormal in all subjects, but highly variable between subjects with the same genetic disorder. A reduced number of residual ‘cones’ was observed in all subjects, albeit to a variable degree; the average diameter of the dark space was consistent with that of normal inner segments at a given eccentricity. The number of waveguiding and non-waveguiding cones was variable, as was the reflectance profile shape of the waveguiding cones.

Conclusions: Here we presented several criteria that can be used to quantify residual photoreceptor structure in subjects with cone degeneration. As gene replacement trials are imminent, it will be of interest to examine how these metrics change following intervention and also determine their relative predictive power for identifying rescuable cones.

1. Dubra A, Harvey Z. Registration of 2D images from fast scanning ophthalmic instruments. Proceedings of the 4th International Conference on Biomedical Image Registration. Heidelberg: Springer-Verlag; 2010: 60–71.