Abstract
Purpose :
Epigenetic remodeling of gene expression is a powerful therapeutic approach. Degenerative diseases of the retina are good candidates for this approach including Retinitis Pigmentosa (RP), for which there are both excellent animal models and an available patient population, but no treatments. We have previously demonstrated the ability of epigenetic modifiers to prevent degeneration of rod photoreceptors in a mouse model of RP, using rd10 mice. Inhibitors of LSD1 and HDAC1 blocked rod degeneration, preserved vision and include maintenance of rod-specific transcripts and downregulation of those involved in inflammation, gliosis, and cell death. To extend our findings we tested the hypothesis that multiple inhibitors of chromatin condensation can prevent photoreceptor degeneration in rd10 mice model.
Methods :
Animal use was in accordance with ARVO/IACUC guidelines. We used daily treatment protocol with 1 injection per day or every other day during 16 days from PN9 to PN24. Mice in each litter was randomly divided to the control and treatment groups. For each litter we had a saline negative control group and a drug treatment experimental group. Experimental groups were injected with DZNep at different concentrations in range of 1-1.5mg/kg or UNC0642 at concentrations of 7.5 mg/kg. Assessment of the changes in retinal histology and gene expression was carried out at PN24
Results :
We have chosen two inhibitors of chromatin condensation that act differently to those we have used previously. The EZH2 is a methytransferase that catalyzes trimethylation of H3K27. It is a component of PRC2 and is critical for both embryonic development and the formation of heterochromatin. DZNep is an inhibitor of EZH2 that selectively blocks formation of H3K27me3 (Ki 50pM). G9A/GLP is a complex that catalyzes methylation of H3K9. The inhibitor UNC0642 is a potent (Ki 4 nM) and selective inhibitor of this complex. Inhibition of G9A/GLP has significant effects on chromatin compaction and gene silencing. Treatment of rd10 mice with both of these inhibitors prevents rod photoreceptors death and increases expression of rod specific genes. Treatment with DZNep additionally decreases expression of inflammation genes.
Conclusions :
Our results provide robust support for our hypothesis that inhibition of chromatin condensation can be sufficient to prevent rod death in rd10 mice.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.