Dry age-related macular degeneration (AMD) is a multifactorial, degenerative retinal-choroidal disease and a leading cause of blindness in the elderly in developed countries. The hallmarks of dry AMD are drusen formation in the early stage and atrophy of the retinal pigment epithelium (RPE), photoreceptors and choriocapillaris in the late stage, also called geographic atrophy. Exposure to the oxidizing agent sodium iodate (NaIO3) leads to dysfunction and death of RPE cells and photoreceptors. After detailed characterization of the acute rat NaIO3 model, this study aimed to identify a compound that can prevent this retinal and RPE damage. Next to this acute model, we also intended to set up a slowly progressing rat NaIO3 model to better mimic the clinical situation.
In the acute model, 10- to 12-week-old male Brown Norway rats received a single intravenous (IV) bolus injection of NaIO3 (40mg/kg) or vehicle (PBS). Compound X was administered intraperitoneally (IP) at the day before (-1dpi), the same day (0dpi) and the day after NaIO3 injection (1dpi), or intravitreally (IVT), at -2dpi and 0dpi. Its efficacy was evaluated up to 7dpi. To establish a slow progression model, NaIO3 was administered via repeated IV injections at 20mg/kg or via osmotic minipump (20 to 90mg/kg/day) for 7 or 14 days. Several non-invasive modalities such as spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) and electroretinography (ERG), complemented with histological analyses, were used to investigate morphological and functional changes.
IVT or IP administration of compound X was able to strongly prevent the acute NaIO3-induced retinal and RPE damage, as observed at both morphological and functional level. In the non-acute setup, repeated IV injections of 20mg/kg NaIO3 did not induce retinal or RPE damage evaluated up to 14dpi. Preliminary experiments with osmotic minipump delivery of NaIO3 starting from 50mg/kg/day showed very minor retinal/RPE changes, yet tolerability issues were observed from 70mg/kg/day onwards.
Conclusion: Acute NaIO3-induced morphological and functional changes of the RPE and neuroretina could strongly and repeatedly be prevented by compound X via different routes of administration. As such, the rat NaIO3 model is appropriate for testing and developing novel drug candidates for prevention of retinal and RPE damage. Experiments are currently being optimized to establish a non-acute NaIO3 model