Residual Foveal Cone Structure in CNGB3 Achromatopsia: Factors for gene therapy candidate selection

Abstract

Purpose: In preparation for gene therapy, quantification of residual cone structure in subjects with CNGB3 achromatopsia (ACHM) is needed. Recent advances in adaptive optics scanning light ophthalmoscopy (AOSLO) have allowed visualization of non-waveguiding photoreceptor structure, even in areas devoid of reflective photoreceptor structure on optical coherence tomography (OCT).¹ Quantifying residual photoreceptor structure is crucial for choosing candidates, targeting treatment , and estimating therapeutic potential.

Methods: Thirty subjects (ages 8-54 years) with CNGB3 ACHM underwent OCT and AOSLO imaging. Presence of foveal hypoplasia and central retinal and photoreceptor complex thicknesses were assessed using OCT. AOSLO was used to probe integrity of the photoreceptor mosaic. Integrity of the ISe, inner segment ellipsoid (IS/OS junction) band was graded using OCT as previously described.² Successful AOSLO imaging was defined as producing interpretable images of the foveal region.

Results: Twenty-five out of 30 subjects had some degree of foveal hypoplasia. Neither the degree of hypoplasia, nor photoreceptor layer thickness, correlated with individual differences in ISe integrity. Foveal montages were successfully obtained using AOSLO in 17 subjects. Peak cone density ranged from no detectable cones to 75,372 cones/mm². While the subject with retinal atrophy (ISe grade 5) had no detectable cones, there was substantial variability in foveal cone density within and across the other ISe grades. For example, the patients with intact ISe had a 4-fold variation in peak cone density.

Conclusions: While AOSLO can be used to image patients with ACHM, it is currently limited to moderately cooperative patients with mild or moderate nystagmus. In extreme cases agreement between ISe integrity and peak cone density exist, however ISe integrity is not always indicative of the density and therefore cannot be used as a reliable biomarker for estimating remnant cone structure. Therefore, cellular imaging appears essential for identifying patients for gene therapy and objective analysis of potential outcomes for a given patient.<br /> 1. Scoles, D.,et al “In vivo imaging of human cone photoreceptor inner segments” IOVS, 55(7): 4244-51 (2014)<br /> 2. Sundaram, V., et al “Retinal structure and function in achromatopsia: implications for gene therapy” Ophthal, 121(1): 234-45 (2014).<br />