Selective Histone Deacetylase 6 Inhibitors Restore Cone Photoreceptor Vision or Outer Segment Morphology in Zebrafish and Mouse Models of Retinal Blindness.

Husvinee Sundaramurthi,Ailis Moran,Sarah L Roche,Giuseppe Campiani,Eugene T Dillion,Breandán N Kennedy,Guinevere L Grice,James A Nathan

doi:10.3389/fcell.2020.00689

Abstract

Blindness arising from retinal or macular degeneration results in significant social, health and economic burden. While approved treatments exist for neovascular (‘wet’) age-related macular degeneration, new therapeutic targets/interventions are needed for the more prevalent atrophic (‘dry’) form of age-related macular degeneration. Similarly, in inherited retinal diseases, most patients have no access to an effective treatment. Although macular and retinal degenerations are genetically and clinically distinct, common pathological hallmarks can include photoreceptor degeneration, retinal pigment epithelium atrophy, oxidative stress, hypoxia and defective autophagy. Here, we evaluated the potential of selective histone deacetylase 6 inhibitors to preserve retinal morphology or restore vision in zebrafish atp6v0e1–/– and mouse rd10 models. Histone deacetylase 6 inhibitor, tubastatin A-treated atp6v0e1–/– zebrafish show marked improvement in photoreceptor outer segment area (44.7%, p = 0.027) and significant improvement in vision (8-fold, p ≤ 0.0001). Tubastatin A-treated rd10/rd10 retinal explants show a significantly (p = 0.016) increased number of outer-segment labeled cone photoreceptors. In vitro, ATP6V0E1 regulated HIF-1α activity, but significant regulation of HIF-1α by histone deacetylase 6 inhibition in the retina was not detected. Proteomic profiling identified ubiquitin-proteasome, phototransduction, metabolism and phagosome as pathways, whose altered expression correlated with histone deacetylase 6 inhibitor mediated restoration of vision.

Highlights

Inherited retinal diseases (IRD) and age-related macular degenerations (AMD) are heterogenous groups of diseases causing blindness
The ability of small molecule HDAC6 inhibitors (TubA, tubacin, ACY-1215 and NF2373) to restore cone photoreceptor vision was evaluated in atp6v0e1−/− zebrafish larvae, a genetic model of blindness potentially relevant to IRD and AMD (Figure 1A)
The maximum tolerated concentration was determined for each HDAC6 inhibitors (HDAC6i), based on the highest concentration exhibiting no adverse effects on gross morphology of ≥ 80% surviving larvae and the average optokinetic response at 5 days post fertilization not reduced by more than 15% (Supplementary Figure S1). atp6v0e1−/− larvae were treated with these maximum tolerated concentrations from 3–6 dpf

Summary

Introduction

Inherited retinal diseases (IRD) and age-related macular degenerations (AMD) are heterogenous groups of diseases causing blindness. A significant milestone was the recent regulatory approval of Luxturna R , a gene therapy for Leber congenital amaurosis patients with recessive mutations in RPE65 (Duncan et al, 2018; Gordon et al, 2019). Drug-based (e.g., neuroprotectants, anti-inflammatory, statins, visual cycle inhibitors, complement inhibitors) clinical trials for IRD and AMD are on-going, albeit many of the previous ones demonstrated limited success (Waugh et al, 2018; Sundaramurthi et al, 2019). This highlights that the vast majority of IRD and dry-AMD patients currently have no access to an effective treatment

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