Epigenetic Modifiers to Treat Retinal Degenerative Diseases

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Retinitis Pigmentosa (RP) is a group of inherited diseases that cause vision loss.
• Previous studies showed LSD1 and HDAC1 inhibitors can prevent rod degeneration in the rd10 mouse model of RP.
• The mechanism underlying this protection may involve altered chromatin structure.

Purpose of the Study:

• To test the hypothesis that inhibiting chromatin condensation prevents photoreceptor degeneration in the rd10 mouse model.
• To investigate the effects of various chromatin condensation inhibitors, including those targeting G9A/GLP and EZH2, on photoreceptor survival.

Main Methods:

• Utilized inhibitors targeting G9A/GLP (H3K9 methylation) and EZH2 (H3K27 trimethylation).
• Compared these inhibitors with those targeting LSD1 and HDAC.
• Administered inhibitors to rd10 mice to assess their impact on photoreceptor degeneration.

Main Results:

• All tested inhibitors, likely decondensing chromatin, preserved retinas to varying degrees in rd10 mice.
• LSD1 and EZH2 inhibitors maintained rod-specific transcripts and activated Ca2+ and Wnt signaling, while inhibiting immune responses.
• HDAC and G9A/GLP inhibitors upregulated NGF-stimulated transcription and downregulated immune response, extracellular matrix, cholesterol signaling, and cell death genes.

Conclusions:

• Inhibition of chromatin condensation is sufficient to prevent rod death in the rd10 mouse model.
• Different chromatin modifiers act through distinct pathways to protect photoreceptors.
• These findings support chromatin structure modulation as a therapeutic strategy for RP.