The promotion of visual function regeneration by intravitreal administration of EA-2353 in animal models of photoreceptor degeneration

Abstract

Purpose : Retinal degeneration associated with photoreceptor loss is a leading cause of visual impairment. EA-2353 is a novel small molecule that is a clinical development candidate for the treatment of retinitis pigmentosa. EA-2353 and its close structural analog CompoundA (CompA) have proliferative effects on progenitor cells in vitroand in vivo. Intravitreal administration of either compound leads to structural improvements in the neural retina in an animal model of retinal degeneration. Here the effects of intravitreal administration of either EA-2353 or CompA on visual and retinal function were assessed in an induced (N-methyl-N-nitrosourea; MNU) and a genetic (Rd10) model of retinal degeneration.

Methods : C57BL/6J mice were administered MNU to induce retinal degeneration. Beginning two weeks after MNU, mice were given 4 weekly intravitreal injections of EA-2353 or vehicle control. Full field electroretinogram (ERG) recordings were performed ~2 weeks after MNU (Post-MNU), and at various time points following the completion of treatment. Visual acuity and contrast sensitivity were assessed by measuring optomotor tracking response thresholds ~ 2 weeks after MNU and at various time points following the completion of treatment.
Rd10 mice (Pde6b^rd10/rd10) were given 4 weekly intravitreal injections of CompA or vehicle control. Following the completion of treatment, ERG recordings were performed.

Results : At ~2 weeks following MNU administration, both groups had equally impaired visual acuity, contrast sensitivity and ERG responses. At various time points following treatment completion (7 – 12 weeks post-MNU), EA-2353 treated eyes had significantly improved visual acuity, contrast sensitivity and ERG responses compared to vehicle controls. Only EA-2353 treated eyes progressively regained previously lost visual/retinal function over time.
In Rd10 mice, eyes treated with CompA had significantly improved ERG responses compared to vehicle controls.

Conclusions : EA-2353 treatment led to the significant regeneration of previously lost visual and retinal function (ERG responses, visual acuity, and contrast sensitivity) in a chemically induced animal model of retinal degeneration. Treatment with an EA-2353 analog (CompA) also led to a significant improvement in ERG responses in a genetic model of retinal degeneration.

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