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