2. Academic Validation
  3. 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

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

  • J Med Chem. 2024 Jul 4. doi: 10.1021/acs.jmedchem.4c00477.
Gabriele Carullo 1,  Noemi Orsini 2 3,  Ilaria Piano 4,  Luca Pozzetti 1,  Alessandro Papa 1,  Anna Fontana 1,  Debora Napoli 2 3,  Francesca Corsi 4,  Beatrice Di Marco 2 3,  Alessia Galante 4,  Ludovica Marotta 1,  Giovanna Panzeca 1,  Justine O'Brien 5,  Alicia Gomez Sanchez 5,  Harry Doherty 5,  Niamh Mahon 5,  Leni Clarke 5,  Chiara Contri 6,  Silvia Pasquini 7,  Beatrice Gorelli 8,  Simona Saponara 8,  Massimo Valoti 8,  Fabrizio Vincenzi 7,  Katia Varani 7,  Anna Ramunno 9,  Simone Brogi 4,  Stefania Butini 1,  Sandra Gemma 1,  Breandán N Kennedy 5,  Claudia Gargini 4,  Enrica Strettoi 2,  Giuseppe Campiani 1 10
Affiliations

Affiliations

  • 1 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 2 Neuroscience Institute, Italian National Research Council (CNR) Area della Ricerca, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy.
  • 3 Regional Doctorate School in Neuroscience of Universities of Florence, Pisa, Siena, Florence, CNR Via Giuseppe Moruzzi 1, 56124 Pisa, Italy.
  • 4 Department of Pharmacy, Via Bonanno 6, 56124 Pisa, Italy.
  • 5 UCD School of Biomolecular and Biomedical Science and UCD Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland.
  • 6 Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
  • 7 Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
  • 8 Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 9 Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84100 Fisciano (SA), Italy.
  • 10 Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 81746-7346, Iran.
PMID: 38961727 DOI: 10.1021/acs.jmedchem.4c00477
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, 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.

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