Purpose
Blindness from geographic atrophy (GA) in Age-related macular degeneration (AMD) remains unaddressed with distinct lack of animal models to evaluate new treatments. GA is thought to result primarily from loss of the retinal pigment epithelium (RPE) and photoreceptors. Current models of AMD like ELOVL4 mutant mice have no visible GA type lesions. Sodium iodate induced RPE/retinal degeneration is non-specific with wide spread damage. Using 810nm diode laser (low xanthophyll and nerve fibre layer absorption), we aimed to recreate the age related loss of RPE/photoreceptors seen in GA in a mouse model.
Methods
C57Bl6 wild mice (female ex-breeders aged 11-13 months, n=24) were used. Confluent diode laser spots (sub-threshold) were applied in 1 quadrant of the retina at 1.3mw power and 60 sec duration each. Color photographs with fluorescein angiography (Micron 3 imaging) and ERG at weeks 8 and 12 were collected. Peanut agglutinin, anti-rhodopsin, histology and transmission electron microscopy (TEM) were used to document the photoreceptor/RPE atrophy. Histological features were compared to human donor eyes with GA.
Results
All laser exposed mouse retinal lesions progressed towards GA type lesions by week 12 (fig 1). The phenotype and histology resembled donor human GA AMD sections (with RPE atrophy and photoreceptor degeneration) (fig 1). ERG was marginally reduced in amplitude with larger GA lesions compared to control eyes. Known features of GA such as atrophy of RPE cells with loss of normal basal infoldings, increase in RPE lysosomes especially at junctional zones (TEM images, fig 2), photoreceptor loss, loss of outer nuclear layer & choroidal thinning could all be demonstrated in mouse study sections (figs 1,2).
Conclusions
Using long wavelength laser, we have created a novel and reproducible mouse model of GA. Such models are crucial for developing and testing therapeutic interventions of autologous or stem cell derived treatments for GA in AMD.