# Targeting AKT via SC79 for Photoreceptor Preservation in Retinitis Pigmentosa Mouse Models

## TL;DR

This study explores using SC79, an AKT activator, to protect photoreceptors in mouse models of retinitis pigmentosa, showing some preservation benefits.

## Contribution

The study demonstrates the therapeutic potential of SC79 in preserving photoreceptors in recessive retinitis pigmentosa models.

## Key findings

- SC79 partially preserved peripheral outer nuclear layer thickness in rd1.GFP mice.
- SC79 improved rod photoreceptor-driven optomotor contrast sensitivity and cone morphology in rd1.GFP mice.
- SC79 restored AKT-related protein expression to uninjected levels or higher in rd1.GFP retinas.

## Abstract

Background/Objectives: Retinitis pigmentosa is a degenerative retinal disease and a major cause of inherited blindness globally. The pro-survival kinase AKT is downregulated in degenerating photoreceptors in retinitis pigmentosa, and its activation has shown neuroprotective effects in retinitis pigmentosa and other neurodegenerative disorders. In this study, we evaluated the therapeutic potential of SC79, a pharmaceutical AKT activator, in two mouse models of retinitis pigmentosa, rd1.GFP and RhoP23H.GFP. Methods: SC79 was administered intravitreally at postnatal day 12 (P12) and analysis was conducted at P16. Results: SC79 at 10 µM was well tolerated in wildtype mice, with no reduction in retinal function or thickness. In rd1.GFP mice, SC79 partially preserved peripheral outer nuclear layer (ONL) thickness, improved rod photoreceptor-driven optomotor contrast sensitivity responses, and improved cone photoreceptor morphology. Immunohistochemistry of retinal sections indicated AKT-related protein expression changes in both sham and SC79-treated rd1.GFP retinas, with sham injections leading to decreases in this pathway and SC79 injections restoring this back to uninjected protein levels or higher, indicating the damage from intravitreal injections can induce AKT-related protein expression changes. In RhoP23H.GFP mice, changes to the visual response from the therapeutic effects of SC79 were not detectable. An increased dosage of SC79 at 100 µM was evaluated in wildtype mice and showed no major toxic effects, although it did not confer neuroprotective benefits in either disease model. Conclusions: These results demonstrate the potential therapeutic effect of AKT pathway modulation for preserving photoreceptors in recessive retinitis pigmentosa, with further optimisation of treatment delivery required.