A canine model for ABCA4 Stargardt disease: in-vivo phenotypic characterization and natural disease history

Abstract

Purpose : A naturally occurring 4176insC in ABCA4 exon 28 results in a frameshift and premature stop, and causes an autosomal recessive retinal degeneration phenotype in dogs, similar to that in human Stargardt disease patients. Natural disease history and phenotypic characterization with in-vivo imaging is presented.

Methods : 8 (5M/3F) ABCA4^ins/ins, 7 (3M/4F) ABCA4^+/ins and 2 (1M/1F) ABCA4^+/+ dogs were evaluated at various time points from 0.4 to 9 years of age with fundus photography, fundus autofluorescence (AF) imaging, optical coherence tomography (OCT), full-field electroretinography (ffERG), multi focal electroretinography (mfERG) and visual behavior.

Results : Fundus examination of ABCA4^ins/ins dogs showed an increased reflectivity and occasional faint darkening within the fovea-like region that advanced to a thin band-shaped streak of reflective changes along the visual streak with a variable progression rate. cSLO AF of ABCA4^ins/ins and ABCA4^+/ins showed a focus of increased autofluorescence in the fovea-like region and along the visual streak as early as 0.4 years. ONL thickness profiles obtained along the vertical meridian showed localized thinning at the visual streak and within the fovea-like region in dogs older than 1 year. Inferior and superior to the visual streak, ONL thickness remained comparable to WT dogs for the first 3 years of life. With time, the ONL thickness declined throughout the vertical meridian. A steep decrease in photopic ffERG response was detected in dogs older than 1 year of age, while the decline in scotopic response was much slower. ABCA4^+/ins and ABCA4^+/+ maintained normal ffERG function. mfERG performed within the temporal quadrant covering the visual streak and fovea like region was comparable in all tested dogs at 0.4 years but was decreased in the ABCA4^ins/ins dogs at 3.6 years. The visual behavior of animals at 2.4 and 3.6 years in both scotopic (0.003lux) and photopic conditions (646lux) was unremarkable. Abnormal scotopic visual behavior was observed in the older dogs at 7.3 years.

Conclusions : The phenotype of the canine model of Stargardt disease is a cone-rod dystrophy with early pathology within the fovea-like region and visual streak characterized by hyper-autofluorescence and ONL thinning. Although a progressive decline in cone-mediated ERG can be detected as early as 1.4 years of age, photopic vision persists for > 9 years.

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