Epigenetic modifiers to treat retinal degenerative diseases

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Retinitis Pigmentosa (RP) is a group of inherited retinal diseases causing progressive vision loss.
• The rd10 mouse model exhibits photoreceptor degeneration, making it a valuable tool for studying RP.
• Previous studies showed LSD1 and HDAC1 inhibitors can protect rod photoreceptors in rd10 mice.

Purpose of the Study:

• To investigate if inhibiting chromatin condensation can prevent photoreceptor degeneration in the rd10 mouse model.
• To explore the effects of various chromatin condensation inhibitors (G9A/GLP, EZH2, LSD1, HDAC1) on retinal health.

Main Methods:

• Utilized rd10 mice, a model for Retinitis Pigmentosa.
• Administered inhibitors targeting chromatin condensation: G9A/GLP (H3K9 methylation), EZH2 (H3K27 trimethylation), LSD1, and HDAC1.
• Assessed retinal preservation, vision maintenance, and changes in gene expression profiles.

Main Results:

• All tested chromatin condensation inhibitors decondensed chromatin and preserved retinas to varying degrees in rd10 mice.
• LSD1 and EZH2 inhibitors maintained rod-specific transcripts, activated Ca+2 and Wnt pathways, and inhibited immune responses.
• HDAC and G9A/GLP inhibitors upregulated NGF-stimulated transcription while downregulating immune response, extracellular matrix, cholesterol signaling, and programmed cell death genes.

Conclusions:

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