Uncovering a Mutation-Independent Therapeutic Strategy against Inherited Retinal Diseases: Development of Class I HDAC/LSD1 Hybrid Inhibitors

Among genetic retinal disorders, retinitis pigmentosa (RP) is characterized by degeneration of rod photoreceptors caused by a large number of diverse mutations, most of which act through different pathways to which epigenetic targets also contribute. The eraser enzymes lysine demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1) play major roles in the development of rod photoreceptors, and their inhibitors were shown to block inherited rod degeneration, preserving vision and contributing to a general anti-inflammatory profile at the retinal level. In this work, we proposed the development of polypharmacological agents targeting class I HDAC/LSD1 enzymes with the aim of treating the rd10 mice model of RP. The new small library of compounds is typified by hybrid (±)-3d, which showed IC50 values of 1702, 842, and 358 nM against HDAC1, HDAC2, and HDAC3, respectively, while inhibiting LSD1 with an IC50 value of 1074 nM. When tested on hydrogen peroxide-stressed ARPE-19 and 661W retinal cells at a concentration of 10 μM, (±)-3d showed a promising antioxidant profile, increasing the cellular levels of acetylated and methylated histone H3, and was selected for further studies also in light of its calculated IH-L. In the rd10 mice RP model, a single intravitreal injection of (±)-3d, at the same concentration used in cells, enhanced photoreceptor survival, downregulated retinal expression of the inflammatory genes GFAP, Ccl2, and Ccl12, and effectively preserved the retinal pigment epithelium barrier. Furthermore, (±)-3d promoted the acetylation and methylation of histone H3, thus confirming the engagement of both class I HDAC and LSD1.