1. 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
- Author
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Carullo, Gabriele, Orsini, Noemi, Piano, Ilaria, Pozzetti, Luca, Papa, Alessandro, Fontana, Anna, Napoli, Debora, Corsi, Francesca, Marco, Beatrice Di, Galante, Alessia, Marotta, Ludovica, Panzeca, Giovanna, O’Brien, Justine, Sanchez, Alicia Gomez, Doherty, Harry, Mahon, Niamh, Clarke, Leni, Contri, Chiara, Pasquini, Silvia, Gorelli, Beatrice, Saponara, Simona, Valoti, Massimo, Vincenzi, Fabrizio, Varani, Katia, Ramunno, Anna, Brogi, Simone, Butini, Stefania, Gemma, Sandra, Kennedy, Breandán N., Gargini, Claudia, Strettoi, Enrica, and Campiani, Giuseppe
- Abstract
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, IC50HDAC6 = 6.32 nM) increased the levels of acetylated α-tubulin compared to histone H3 in ARPE-19 and 661W cells. 5dpromoted vision rescue in the atp6v0e1–/–zebrafish model of photoreceptor dysfunction. A single intravitreal injection of 5din the rd10mouse model of RP supported morphological and functional preservation of cone cells and maintenance of the retinal pigment epithelium array.
- Published
- 2024
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