ORY-1001 Delays Retinal Photoreceptor Degeneration in rd10 Mice 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.