Effect of HDAC inhibition on a model of dry AMD in the presence of systemic inflammation

Abstract

Purpose : Age-related macular degeneration (AMD) and rheumatoid arthritis (RA) share many risk factors, and are characterized by similar inflammatory responses. Our previous in vivo research identified increased retinal degeneration and cytokine response in a mouse model of dry AMD in the presence of systemic inflammation from RA. Histone deacetylases (HDACS) are enzymes capable of regulating cytokine production via reducing acetylation, and are found to be dysregulated in various inflammatory diseases including RA and AMD. Therefore, this current study investigates the effect of HDAC inhibition on AMD progression in the presence of systemic inflammation.

Methods : Collagen induced arthritis (CIA) was induced in male and female C57BL/6J mice using an emulsion of complete Freund's adjuvant and type II collagen. Following development of CIA, retinal degeneration by sodium iodate (NaIO₃; dry AMD model) was performed in the presence or absence of a selective HDAC class I (HDAC1 and HDAC3) inhibitor, MS-275 (Entinostat). Retinal function was assessed by electroretinography (ERG), structure by optical coherence tomography (OCT), and molecular analysis by RT-qPCR.

Results : NaIO₃ induced retinal damage was significantly diminished in CIA mice treated with MS-275 compared to vehicle-treated control. Here we found a significant improvement in outer nuclear layer thickness (p ≤ 0.001), which was reflected in improvement of overall whole retinal thickness (p ≤ 0.001). While no significant difference was observed in RPE function following CIA + NaIO₃ treatment in the presence of MS-275, a trend in increased c-wave amplitude was detected. Lastly, we identified a decrease in C-X-C chemokine ligand 9 (Cxcl9) expression in CIA + NaIO₃ mouse retinal pigment epithelium (RPE)/choroid in the presence of MS-275 when compared to vehicle treated mice (p ≤ 0.05).

Conclusions : Our OCT analysis demonstrates that HDAC inhibition is capable of reducing the additive effect of NaIO₃ induced retinal degeneration in the presence of systemic inflammation by CIA. In addition, HDAC inhibition in the CIA + NaIO₃ treated mice resulted in reduced cytokine expression. These findings are highly innovative and provide additional support to the therapeutic potential of HDAC inhibitors for the treatment of dry AMD, and highlight the importance of understanding the role of systemic inflammation on dry AMD progression.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.