Increased H3K27 trimethylation contributes to cone survival in a mouse model of cone dystrophy.

Inherited retinal diseases (IRDs) are a heterogeneous group of blinding disorders, which result in dysfunction or death of the light-sensing cone and rod photoreceptors. Despite individual IRDs (Inherited retinal disease) being rare, collectively, they affect up to 1:2000 people worldwide, causing a significant socioeconomic burden, especially when cone-mediated central vision is affected. This study uses the Pde6ccpfl1 mouse model of achromatopsia, a cone-specific vision loss IRD (Inherited retinal disease), to investigate the potential gene-independent therapeutic benefits of a histone demethylase inhibitor GSK-J4 on cone cell survival. We investigated the effects of GSK-J4 treatment on cone cell survival in vivo and ex vivo and changes in cone-specific gene expression via single-cell RNA sequencing. A single intravitreal GSK-J4 injection led to transcriptional changes in pathways involved in mitochondrial dysfunction, endoplasmic reticulum stress, among other key epigenetic pathways, highlighting the complex interplay between methylation and acetylation in healthy and diseased cones. Furthermore, continuous administration of GSK-J4 in retinal explants increased cone survival. Our results suggest that IRD (Inherited retinal disease)-affected cones respond positively to epigenetic modulation of histones, indicating the potential of this approach in developing a broad class of novel therapies to slow cone degeneration.

HDAC Inhibition Prevents Primary Cone Degeneration Even After the Onset of Degeneration.

Cone photoreceptor loss is the main cause of color blindness and loss of visual acuity in patients suffering from inherited cone dystrophies. Despite the crucial role of cones in everyday life, knowledge on mechanisms of cone cell death and the identification of potential targets for the preservation or delay of cone loss are scarce. Recent findings have shown that excessive histone deacetylase (HDAC) activity is associated with both primary rod and primary cone degeneration. Importantly, pharmacological inhibition of HDAC activity in vivo at the onset of cone degeneration offers a prolonged protection of cones in a mouse model of inherited cone degeneration (cpfl1). In this study, we evaluated the potential of trichostatin A (TSA), a pan-HDAC inhibitor, to prevent cone cell death at a later stage of degeneration in the cpfl1 model. We demonstrate that a single intravitreal TSA injection protected the cpfl1 cones even when administered after the onset of degeneration. In addition, the TSA treatment significantly improved aberrant cone nucleokinesis present in the cpfl1 retina. These results highlight the feasibility of targeted cone neuroprotection in vivo even at later disease stages of inherited cone dystrophies.