# ORY-1001 Delays Retinal Photoreceptor Degeneration in rd10 Mice by Inhibiting H3K4me2 Demethylation

## TL;DR

ORY-1001 delays retinal degeneration in rd10 mice by inhibiting H3K4me2 demethylation, suggesting a new epigenetic treatment for retinitis pigmentosa.

## Contribution

This is the first study to show ORY-1001's effectiveness in treating retinitis pigmentosa in animal models.

## Key findings

- ORY-1001 improved electroretinogram responses and visual behavior in rd10 mice.
- Chromatin accessibility and gene expression related to metabolism were altered in treated mice.
- Increased H3K4me2 and CoREST protein expression was observed in retinal tissue.

## Abstract

Our research shows that ORY-1001 delays the process of retinal photoreceptor degeneration in rd10 mice, a mouse model of retinitis pigmentosa (RP). To the best of our knowledge, besides treating acute myeloid leukemia and certain solid tumors in clinical trials, this is the first study to demonstrate that ORY-1001 is effective in treating RP in animal experiments, which is relevant for metabolism. Our primary results suggest that a new and novel epigenetic therapy for RP is possible, simply by inhibiting H3K4me2 demethylation.

(1) Background: Modifications of histone methylation could alter chromatin structure and thereby have an impact on gene expressions. (2) Methods: To investigate whether ORY-1001 delay retinal photoreceptor degeneration, rd10 mice were intraperitoneally injected with ORY-1001 (0.075 mg/kg) every second day from the 14th to the 24th day after birth. Full-field electroretinogram detection (ff ERG), optical coherence tomography (OCT), visual behavioral testing, retinal tissue morphology observation, and protein expression detection experiments were performed on the 25th day. Simultaneously, ATAC-seq and RNA-seq were used to test the mice’s retinal tissues, and metabolomics detection and quantitative real-time polymerase chain reaction (qRT-PCR) were carried out. (3) Results: Compared with the rd10 group, in the treatment group, the function in the electroretinogram response and the visual behavioral responses were improved, the nuclear layer morphology of retinal tissue was reserved more, and the protein expression of H3K4me2 and CoREST was increased. Conjoint analysis of our ATAC-seq and RNA-seq results showed that chromatin accessibility was changed, as was gene expression which was involved in metabolism changes. In addition, the effector gene in the retina was Gnat1. (4) Conclusions: ORY-1001 delays retinal photoreceptor degeneration by inhibiting H3K4me2 demethylation in rd10 mice, which suggests that ORY-1001, as a novel epigenetic modifier, has potential for treating RP.