Longitudinal characterization of retinal degeneration in a nonhuman primate model of Batten disease.

Abstract

Purpose : We previously discovered a naturally occurring Japanese macaque model of CLN7 Batten disease with the hallmark features of the human disease, including retinal and CNS neurodegeneration. This study characterized the retinal degeneration longitudinally with multimodal retinal imaging and electrophysiology and correlated these findings with histology.

Methods : Retinal structure and function of 7 CLN7^-/- monkeys were examined every 6 months from 2 months to 5 years of age and compared with WT controls. Fundus autofluorescence (FAF) was measured quantitatively, and OCT scans were used to quantify retinal layer thicknesses within the central 1 mm (fovea) and the 1-3 mm and 3-6 mm annuli of the macula. Central macular cone function was assessed by multifocal electroretinography (mfERG), and rod and cone function by photopic and scotopic full-field ERG.

Results : At 2 months, punctate fluorescence was visible across the posterior retina in FAF images. Mean FAF levels in CLN7^-/- monkeys were similar to controls at 2 months, but increased at a 9-fold higher rate than in control monkeys. Photoreceptor layer thickness of CLN7^-/- animals were within the normal range; only the outer 3-6mm macula decreased ~3% annually. Inner retinal layers thinned ~5% per year, but the central 1mm fovea was preserved. The INL, where hyper-reflective spots were prominent, thinned ~10% per year. As degeneration progressed, layer lamination became indistinct, particularly in the INL, IPL, and ELM. Multifocal ERG amplitudes remained within normal limits until 1 year but decreased at later ages, with only foveal function being preserved. Full-field ERG photopic and bright-flash scotopic a- and b-waves were within the normal range at 6 months, but decreased ~15% (a-wave) and 20% (b-wave) per year, while dim-flash scotopic b-wave amplitudes decreased by 15-35% per year. In tissue, punctate autofluorescence was associated with accumulation of lysosomal storage deposits within the INL/IPL, and high autofluorescence was also observed in photoreceptor inner segments and RPE. Thinning of INL/IPL seen in vivo correlated with tissue analysis, and both correlated closely with OCT and ERG data.

Conclusions : In CNL7^-/- monkeys, elevated fundus autofluorescence and inner retinal thinning were detectable early. This quantitative characterization provides a foundation for assessing the effectiveness of therapeutic interventions.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.