Targeting Relevant HDACs to Support the Survival of Cone Photoreceptors in Inherited Retinal Diseases: Identification of a Potent Pharmacological Tool with In Vitro and In Vivo Efficacy

Inherited
retinal diseases, which include retinitis pigmentosa,
are a family of genetic disorders characterized by gradual rod-cone
degeneration and vision loss, without effective pharmacological treatments.
Experimental approaches aim to delay disease progression, supporting
cones’ survival, crucial for human vision. Histone deacetylases
(HDACs) mediate the activation of epigenetic and nonepigenetic pathways
that modulate cone degeneration in RP mouse models. We developed new
HDAC inhibitors (5a–p), typified
by a tetrahydro-γ-carboline scaffold, characterized by high
HDAC6 inhibition potency with balanced physicochemical properties
for in vivo studies. Compound 5d (repistat, IC50 HDAC6 = 6.32 nM) increased the levels of acetylated
α-tubulin compared to histone H3 in ARPE-19 and 661W cells. 5d promoted vision rescue in the atp6v0e1–/– zebrafish model of
photoreceptor dysfunction. A single intravitreal injection of 5d in the rd10 mouse model of RP supported
morphological and functional preservation of cone cells and maintenance
of the retinal pigment epithelium array.