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1. HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

Author

Pro Retina Foundation, Tistou and Charlotte Kerstan Foundation, German Research Foundation, Swiss National Science Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Samardzija, Marijana [0000-0003-0991-4653], Corna, Andrea [0000-0002-3209-6719], Gómez-Sintes, Raquel [0000-0003-2854-6964], Jarboui, Mohamed Ali [0000-0002-5203-235X], Armento, Angela [0000-0002-6357-1500], Haq, Wadood [0000-0003-0890-9780], Paquet-Durand, Francois [0000-0001-7355-5742], Zrenner, Eberhart [0000-0003-2846-9663], de la Villa, P. [0000-0001-9856-6616], Zeck, Günther [0000-0003-3998-9883], Grimm, Christian [0000-0001-9318-4352], Boya, Patricia [0000-0003-3045-951X], Ueffing, Marius [0000-0003-2209-2113], Trifunovic, Dragana [0000-0003-3168-4196], Samardzija, Marijana, Corna, Andrea, Gómez-Sintes, Raquel, Jarboui, Mohamed Ali, Armento, Angela, Roger, Jerome E., Petridou, Eleni, Haq, Wadood, Paquet-Durand, Francois, Zrenner, Eberhart, de la Villa, P., Zeck, Günther, Grimm, Christian, Boya, Patricia, Ueffing, Marius, Trifunovic, Dragana, Pro Retina Foundation, Tistou and Charlotte Kerstan Foundation, German Research Foundation, Swiss National Science Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Samardzija, Marijana [0000-0003-0991-4653], Corna, Andrea [0000-0002-3209-6719], Gómez-Sintes, Raquel [0000-0003-2854-6964], Jarboui, Mohamed Ali [0000-0002-5203-235X], Armento, Angela [0000-0002-6357-1500], Haq, Wadood [0000-0003-0890-9780], Paquet-Durand, Francois [0000-0001-7355-5742], Zrenner, Eberhart [0000-0003-2846-9663], de la Villa, P. [0000-0001-9856-6616], Zeck, Günther [0000-0003-3998-9883], Grimm, Christian [0000-0001-9318-4352], Boya, Patricia [0000-0003-3045-951X], Ueffing, Marius [0000-0003-2209-2113], Trifunovic, Dragana [0000-0003-3168-4196], Samardzija, Marijana, Corna, Andrea, Gómez-Sintes, Raquel, Jarboui, Mohamed Ali, Armento, Angela, Roger, Jerome E., Petridou, Eleni, Haq, Wadood, Paquet-Durand, Francois, Zrenner, Eberhart, de la Villa, P., Zeck, Günther, Grimm, Christian, Boya, Patricia, Ueffing, Marius, and Trifunovic, Dragana

Abstract

Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways,including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages.

Published
2020

2. HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

Author

Jerome E. Roger, Angela Armento, Eleni Petridou, Patricia Boya, Marijana Samardzija, Raquel Gómez-Sintes, Eberhart Zrenner, Marius Ueffing, Dragana Trifunović, Christian Grimm, Wadood Haq, Andrea Corna, Mohamed Ali Jarboui, Günther Zeck, François Paquet-Durand, Pedro de la Villa, University of Zurich, Trifunović, Dragana, Pro Retina Foundation, Tistou and Charlotte Kerstan Foundation, German Research Foundation, Swiss National Science Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Samardzija, Marijana, Corna, Andrea, Gómez-Sintes, Raquel, Jarboui, Mohamed Ali, Armento, Angela, Haq, Wadood, Paquet-Durand, Francois, Zrenner, Eberhart, de la Villa, P., Zeck, Günther, Grimm, Christian, Boya, Patricia, Ueffing, Marius, Trifunovic, Dragana, Samardzija, Marijana [0000-0003-0991-4653], Corna, Andrea [0000-0002-3209-6719], Gómez-Sintes, Raquel [0000-0003-2854-6964], Jarboui, Mohamed Ali [0000-0002-5203-235X], Armento, Angela [0000-0002-6357-1500], Haq, Wadood [0000-0003-0890-9780], Paquet-Durand, Francois [0000-0001-7355-5742], Zrenner, Eberhart [0000-0003-2846-9663], de la Villa, P. [0000-0001-9856-6616], Zeck, Günther [0000-0003-3998-9883], Grimm, Christian [0000-0001-9318-4352], Boya, Patricia [0000-0003-3045-951X], Ueffing, Marius [0000-0003-2209-2113], and Trifunovic, Dragana [0000-0003-3168-4196]

Subjects
10018 Ophthalmology Clinic, MAPK/ERK pathway, Programmed cell death, genetic structures, 610 Medicine & health, Biology, Article, Photoreceptor cell, 1307 Cell Biology, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Retinitis pigmentosa, 1312 Molecular Biology, medicine, Animals, Molecular Biology, 030304 developmental biology, Mice, Inbred C3H, 0303 health sciences, Autophagy, Retinal, Cell Biology, medicine.disease, Cone cell, ddc, 3. Good health, Cell biology, Histone Deacetylase Inhibitors, Mice, Inbred C57BL, Disease Models, Animal, Neuroprotective Agents, medicine.anatomical_structure, Histone, Gene Expression Regulation, chemistry, Intravitreal Injections, Retinal Cone Photoreceptor Cells, biology.protein, sense organs, Neurological disorders, Retinitis Pigmentosa, 030217 neurology & neurosurgery, Neuroscience
Abstract

16 p.-7 fig., Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways,including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages., This work was supported by the ProRetina foundation,the Kerstan Foundation, Deutsche Forschungsgemeinschaft (DFGTR 1238/4-1), Swiss National Science Foundation (31003A_173008),BMBF (FKZ: 01EK1613E), and GC2018-098557-B-I00 from MCIU/AEI/FEDER, UE. RGS is a recipient of a JIN grant RTI2018-098990- J-I00 from MCIU, Spain.

Published
2020

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