Clinical researchers at the University College London, with Moorfields Eye Hospital and Guy’s and St. Thomas’, have reported a valuable correlation between anatomical measurement and functional analysis to provide robust metrics which may determine the impact of interventions. The anatomical ellipsoid zone (EZ) in the retina, identifiable by SD-OCT analysis, identifies the photoreceptor layer (rods and cones) and these EZ width (EZW) and EZ area (EZA) measurements can be compared between baselines and later timepoints, and subsequently compare and collate with other patient measurements. Most importantly, the EU EMA and the US FDA regulatory authorities accept these metrics as clinical trial outcome measures. In combination with EZW and EWA activity, research can now quantify total retinal and outer nuclear layer foveal thickness and correlate these measures with visual acuity and retinal sensitivity.
Leber congenital amaurosis (LCA) is a mostly recessive childhood-onset retinal dystrophy affecting rod and cone photoreceptors. It is a severe pathology that typically becomes evident in the first year of life and is characterised by poor visual function, nystagmus, sluggish pupillary responses, photophobia and hyperopia. In addition, the electroretinogram (ERG) is characteristically “non-detectable” or severely subnormal and the disorder affects between 1/33,000 and 1/81,000 live births. LCA are caused by mutations within 25 genes,accounting for 70%-80% of individuals with LCA, one gene of which – retinal pigment epithelium 65 (RPE65) – is linked to ~5% of all LCA cases. In the current clinical study, the UK research team assessed twenty-six subjects with LCA-RPE65 recording SD-OCT and FAF imaging, including measurement of foveal thickness (FT), outer nuclear layer thickness (ONLT), ellipsoid zone width (EZW) and ellipsoid zone area (EZA) analysis.
The results of the study showed that EZW and EZA were measurable in 67% (35/52) and 37% (19/52) of patient eyes, respectively, and this analysis had good agreement on repeated measurements. The annual rate of progression using EZW was −300.63 μm/year, and −1.17 mm2/year in EZA. EZW was found to have a statistically significant (P < 0.05) correlation with BCVA (r = −0.52, P = 0.03) and retinal sensitivity V30 (r = 0.57, P = 0.02). This suggests that patients with wider EZW and thereby greater preservation of retinal structure have better BCVA and larger volumes of retinal sensitivity. There was no correlation between age and any OCT metrics. Thisstudy provides a natural history metric which can track the data of measurement for clinical management and, significantly, uses EZW correlation with functional assessment to measure clinical trial outcomes for RPE65 populations. In conclusion, the results of the study suggest EZW to be a better metric for quantifying retinal degeneration, compared to the other three measurements (foveal thickness, ONL thickness and EZA). In the closing remarks of the report, the authors stated that, “retinal integrity will be important in identifying and monitoring subjects with RPE65-RD in both treatment and clinical trial settings – both in terms of safety, but moreover, in terms of addressing one of the primary clinical objectives of slowing or halting otherwise inexorable retinal degeneration”.