Investigating the neuroprotective capabilities of a histone demethylase inhibitor in three mouse models of cone dystrophy

Abstract

Purpose : We recently reported that H3K27 trimethylation was present in wildtype cones, but a distinct reduction was observed in the cones of the Pde6c^cpfl1 cone dystrophy mouse, potentially leading to pathogenicity in the degenerating cones (Miller et al. 2022). We also showed that treating Pde6c^cpfl1 retinas with GSK-J4, a histone demethylase inhibitor, led to a significant increase in cone survival, unlocking a potential neuroprotective treatment for cone dystrophy. Here we investigated the therapeutic effect of GSK-J4 on two other cone dystrophy models and tested if GSK-J4 can be provided later in the disease progression and still exert a beneficial function.

Methods : We used three mouse models of cone dystrophy, Gnat2^cpfl3.GFP, Cnga3^-/-.GFP and Pde6c^cpfl1.GFP, herein referred to as Gnat2.GFP, Cnga3.GFP and Pde6c.GFP. Each model has a different disease progression, Pde6c.GFP cones degenerating the fastest and Gnat2.GFP the slowest. Consequently, we administered a single intravitreal injection of GSK-J4 or a sham injection at P40-45 in Pde6c.GFP mice, P60-65 in Cnga3.GFP mice, and between P70-P75 in Gnat2.GFP mice. After four days, ERGs were performed before histological and molecular processing of the retinas.

Results : After treatment with GSK-J4 we saw a 10.6% increase in cone survival in Gnat2.GFP mice, compared to sham controls (n=5, Welch’s T-test, P=0.0469). In contrast, the Pde6c.GFP and Cnga3.GFP models did not show a significant improvement in cone numbers with treatment (n=5, Welch’s T-test, P>0.05). ERG responses (n=4, two-way ANOVA, P>0.05) and retinal stress markers were similar between sham-injected mice and GSK-J4 treated mice in all three models, suggesting no significant deleterious effects of GSK-J4.

Conclusions : We saw that late administration of GSK-J4 in Pde6c.GFP and Cnga3.GFP mice did not improve cone survival, potentially from the cones being too degenerated at this point of disease progression. Interestingly, GSK-J4 displayed neuroprotective capabilities in the Gnat2.GFP mouse model, which has a slow rate of cone degeneration. This suggests that while GSK-J4 has shown neuroprotective potential, it may be a stronger drug candidate when provided earlier in disease progression. Molecular analysis is currently underway to identify the differences in pathways affected after treatment in each model.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.