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

Samardzija, Marijana; Masarini, Klaudija; Ueffing, Marius; Trifunović, Dragana

doi:10.1007/978-3-030-27378-1_63

Cited by 7 publications

(8 citation statements)

References 14 publications

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“…Therefore, a treatment even at late stages of the disease is likely to be beneficial [48]. Indeed, our data on HDAC-induced cone protection at different stages of rd1 TN-XL cone loss (PN19 and PN21) confirm this and is furthermore in line with other observations indicating that the window-of-opportunity for the treatment of retinal dystrophies is much broader than it is currently considered [2,49].…”

Section: Discussionsupporting

confidence: 90%

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 90%

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

et al. 2020

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“…The overexpression of HDAC4 in electroporated rd1 mouse retinas could prolong the photoreceptor survival in a way that might be related to hypoxia-inducible factor 1α activity in the cytoplasm [66] . These results seem to be different from previous data [34,57,67] , which showed that the inhibition of HDACs could protect photoreceptors from degeneration under certain conditions. One explanation may be that HDAC4 plays a neuroprotective role for photoreceptors when it is located in the cytoplasm, which indicates that its substrates are not histone proteins.…”

Section: Effects Of Hdacs and Hats On Photoreceptor Degeneration Undcontrasting

confidence: 99%

The Role of Histone Acetyltransferases and Histone Deacetylases in Photoreceptor Differentiation and Degeneration

Zhao¹,

Tao²,

Peng³

2020

Int. J. Med. Sci.

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Photoreceptors are critical components of the retina and play a role in the first step of the conversion of light to electrical signals. The differentiation and degeneration of photoreceptors are regulated by specific genes and proteins. With the development of epigenetic approaches, scientists have discovered that histone modifications, such as acetylation, methylation, ubiquitylation, and phosphorylation, may modulate the processes of photoreceptor differentiation and degeneration. Histone acetylation is regulated by two opposing classes of enzymes, namely, histone acetyltransferases (HATs) and histone deacetylases (HDACs), which add and remove acetyl groups to and from target histones, respectively, causing changes in transcriptional activity. Herein, we review the effects of HATs and HDACs on the differentiation and degeneration of photoreceptors and discuss the underlying mechanisms of these effects.

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“…Recent investigations into neuroprotective strategies suggest that histone deacetylase (HDAC) inhibition slows rod and cone photoreceptor degeneration in different murine models of retinal dystrophies, revealing a promising alternative solution for cone-rod dystrophies ( Mitton et al, 2014 ; Samardzija et al, 2019 ; Trifunović et al, 2016 ). However, the neuroprotective strategies for USH2A -related patients are only relevant in the early stages of RP.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

USH2A-retinopathy: From genetics to therapeutics

Toualbi

Toms

Moosajee

2020

Experimental Eye Research

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Bilallelic variants in the USH2A gene can cause Usher syndrome type 2 and non-syndromic retinitis pigmentosa. In both disorders, the retinal phenotype involves progressive rod photoreceptor loss resulting in nyctalopia and a constricted visual field, followed by subsequent cone degeneration, leading to the loss of central vision and severe visual impairment. The USH2A gene raises many challenges for researchers and clinicians due to a broad spectrum of mutations, a large gene size hampering gene therapy development and limited knowledge on its pathogenicity. Patients with Usher type 2 may benefit from hearing aids or cochlear implants to correct their hearing defects, but there are currently no approved treatments available for the USH2A -retinopathy. Several treatment strategies, including antisense oligonucleotides and translational readthrough inducing drugs, have shown therapeutic promise in preclinical studies. Further understanding of the pathogenesis and natural history of USH2A -related disorders is required to develop innovative treatments and design clinical trials based on reliable outcome measures. The present review will discuss the current knowledge about USH2A , the emerging therapeutics and existing challenges.

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

Cited by 7 publications

References 14 publications

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

The Role of Histone Acetyltransferases and Histone Deacetylases in Photoreceptor Differentiation and Degeneration

USH2A-retinopathy: From genetics to therapeutics

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