HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

• Published in: Cell death and differentiation 2021-04, Vol.28 (4), p.1317-1332
• Main Authors: Samardzija, Marijana, Corna, Andrea, Gomez-Sintes, Raquel, Jarboui, Mohamed Ali, Armento, Angela, Roger, Jerome E., Petridou, Eleni, Haq, Wadood, Paquet-Durand, Francois, Zrenner, Eberhart, de la Villa, Pedro, Zeck, Günther, Grimm, Christian, Boya, Patricia, Ueffing, Marius, Trifunović, Dragana
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/106; 13/31; 14/63; 38/39; 38/91; 631/378; 64/60; 692/699/375; 9/30; Acuity; AKT protein; Animal models; Animals; Apoptosis; Autophagy; Biochemistry; Biomedical and Life Sciences; Blindness; Cell Biology; Cell culture; Cell Cycle Analysis; Cell death; Color vision; Cones; Disease; Disease Models, Animal; Gene Expression Regulation - drug effects; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histones; Intravitreal Injections; Life Sciences; MAP kinase; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mutation; Neuroprotective Agents - pharmacology; Phagocytosis; Phosphodiesterase; Photoreceptors; Retinal Cone Photoreceptor Cells - drug effects; Retinitis; Retinitis pigmentosa; Retinitis Pigmentosa - drug therapy; Retinitis Pigmentosa - pathology; Stem Cells; Structure-function relationships; Visual perception
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-020-00653-3

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.