Uncovering a Mutation-Independent Therapeutic Strategy against Inherited Retinal Diseases: Development of Class I...

Area of Science:

• Genetics
• Neuroscience
• Pharmacology

Background:

• Retinitis pigmentosa (RP) is a group of genetic retinal disorders characterized by rod photoreceptor degeneration.
• Epigenetic mechanisms, including targets of histone deacetylase 1 (HDAC1) and lysine demethylase 1 (LSD1) enzymes, play a role in RP pathogenesis.
• Inhibitors of HDAC1 and LSD1 have demonstrated potential in blocking inherited retinal degeneration and reducing inflammation.

Purpose of the Study:

• To develop novel polypharmacological agents targeting class I HDAC/LSD1 enzymes for the treatment of RP.
• To evaluate the efficacy of these agents in the rd10 mice model of RP.

Main Methods:

• Synthesis of a small library of hybrid compounds targeting HDAC1/LSD1.
• Biochemical assays to determine inhibitory concentrations (IC₅₀) against HDAC1, HDAC2, HDAC3, and LSD1.
• In vitro testing on retinal cells (ARPE-19 and 661W) to assess antioxidant properties and effects on histone acetylation and methylation.
• In vivo studies in rd10 mice involving intravitreal injection to evaluate photoreceptor survival, gene expression of inflammatory markers, and retinal pigment epithelium barrier integrity.

Main Results:

• The hybrid compound (±)-3d demonstrated potent inhibition of HDAC1, HDAC2, HDAC3, and LSD1.
• (±)-3d exhibited antioxidant properties in retinal cells and increased histone H3 acetylation and methylation.
• In rd10 mice, a single intravitreal injection of (±)-3d preserved photoreceptor survival, downregulated inflammatory gene expression (GFAP, Ccl2, Ccl12), and maintained the retinal pigment epithelium barrier.
• (±)-3d treatment confirmed engagement of both class I HDAC and LSD1 targets through increased histone H3 acetylation and methylation.

Conclusions:

• Polypharmacological agents targeting class I HDAC/LSD1 enzymes represent a promising therapeutic strategy for retinitis pigmentosa.
• (±)-3d is a potent inhibitor of HDAC1/LSD1 with demonstrated efficacy in preserving vision and reducing retinal inflammation in an RP mouse model.
• Further investigation of (±)-3d and similar compounds is warranted for the treatment of RP and other genetic retinal disorders.