A laser-induced mouse model of progressive retinal degeneration with central sparing displays features of parafoveal geographic atrophy

Abstract

There are no disease-modifying treatments available for geographic atrophy (GA), the advanced form of dry age-related macular degeneration. Current murine models fail to fully recapitulate the features of GA and thus hinder drug discovery. Here we describe a novel mouse model of retinal degeneration with hallmark features of GA. We used an 810 nm laser to create a retinal lesion with central sparing (RLCS), simulating parafoveal atrophy observed in patients with progressive GA. Laser-induced RLCS resulted in progressive GA-like pathology with the development of a confluent atrophic lesion. We demonstrate significant changes to the retinal structure and thickness in the central unaffected retina over a 24-week post-laser period, confirmed by longitudinal optical coherence tomography scans. We further show characteristic features of progressive GA, including a gradual reduction in the thickness of the central, unaffected retina and of total retinal thickness. Histological changes observed in the RLCS correspond to GA pathology, which includes the collapse of the outer nuclear layer, increased numbers of GFAP + , CD11b + and FcγRI + cells, and damage to cone and rod photoreceptors. We demonstrate a laser-induced mouse model of parafoveal GA progression, starting at 2 weeks post-laser and reaching confluence at 24 weeks post-laser. This 24-week time-frame in which GA pathology develops, provides an extended window of opportunity for proof-of-concept evaluation of drugs targeting GA. This time period is an added advantage compared to several existing models of geographic atrophy.

Photoreceptor loss does not recruit neutrophils despite strong microglial activation

“…61,62 Since then, it has been a popular damage model. Focal lesions in the retina have been conducted in a number of popular animal models including mouse 63,64 , macaque [65][66][67] and cats. 68,69 Laser damage is also clinically relevant as it is both experienced with accidental laser exposure 70,71 as well as purposeful ablation used in photocoagulation and as a therapy for retinal ischemic disease, retinopathy of prematurity 72 and diabetic retinopathy 73 .…”