Optimization of the dry age-related macular degeneration model in Cynomolgus monkeys by intravitreal injection of sodium iodate

Abstract

Purpose : Dry age-related macular degeneration (dAMD) model in non-human primates (NHP) could be developed through sodium iodate (SI) administration intravitreally. However even with the suggested doses, this model showed significant individual variation, which affects pharmacodynamics evaluation. This study aimed to optimize the SI induced dAMD model in NHPs through managing the injection location and speed.

Methods : Cynomolgus monkeys were administered intravitreally with sodium iodate (0.4~1.6 mg in 100uL/eye) above the macular area of unilateral eye. The injection was applied within 30 seconds. Fundus photography (FP), optical coherence tomography (OCT), fluorescein fundus angiography (FFA), electroretinography (ERG) and fundus auto-fluorescence (FAF) were conducted before the injection and at 1, 2, 4, 6, 8, 12 weeks after the injection. A complement C5 protein inhibitor was administered to one SI-treated eye (1.2 mg/eye) at one week post-modelingfor verification purpose. The RPE, photoreceptor cells and vascular changes are further quantitatively analyzed in-vivo by using adaptive optics scanning laser ophthalmoscope (AOSLO) reflectance and autofluorescence mode.

Results : Retinal lesion in the macular area was observed as early as 1 week-post injection in the eyes dosed at 0.8 mg/eye and above.
The severity of retinal lesions was dose dependent, ranging from undetectable changes (0.4mg/eye), mild changes (0.8mg/eye), geographic atrophy (1.2mg/eye) to severe geographic atrophy (1.6 mg/eye). The lesion with 0.8mg/eye showed reversibility post Week 4. ERG results showed a significant decrease of amplitude even disappearance of signal indicating impaired retinal function. The changes are summarized in the Table.
Administration of complement C5 protein inhibitor significantly improved retinal morphology, although did not lead to substantial improvement in retinal function.
Cellular-level disruptions to RPE, photoreceptor and vascular changes are observed in all retinal lesion areas.

Conclusions : Through managing the SI injection location and speed, various dosages of SI induced various severities of dAMD in NHPs. The ocular changes observed was similar to some of features seen in patients with dAMD. The non-human primate model provides a quantitative and translational model for research and development of ophthalmological drugs.

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