ROCK inhibitors for the treatment of ocular diseases

Nourinia, Ramin; Nakao, Shintaro; Zandi, Souska; Safi, Sare; Hafezi-Moghadam, Ali; Ahmadieh, Hamid

doi:10.1136/bjophthalmol-2017-310378

Cited by 24 publications

(21 citation statements)

References 65 publications

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“…Future studies are needed to validate the isoform-specificity, the potential therapeutic value and the off-target effects of SR-3677. This is also true for the many new ROCK inhibitors, which have been developed in the last few years, mainly driven by their promising therapeutic effect in the treatment of glaucoma [49]. Independent of their chemistries, they all act as ATP competitors, and thus off-target effects are almost inevitable.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Santos

Hartmann

Zimmermann

et al. 2019

Journal of Molecular and Cellular Cardiology

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Cardiac fibrosis is a hallmark of heart failure for which there is no effective pharmacological therapy. By genetic modification and in vivo inhibitor approaches it was suggested that the Rho-associated kinases (ROCK1 and ROCK2) are involved in pro-fibrotic signalling in cardiac fibroblasts and that they may serve as targets for anti-fibrotic therapies. We demonstrate that simultaneous inhibition of ROCK1 and ROCK2 strongly interfered with tissue formation and their biomechanical properties in a model of engineered connective tissue (ECT), comprised of cardiac fibroblasts and collagen. These effects were observed with both rat and human ECT. Inhibitors of different chemistries, including the isoquinoline inhibitors Fasudil and H1152P as well as the pyrazol-phenyl inhibitor SR-3677, showed comparable effects. By combined treatment of ECT with TGF-β and H1152P, we could identify ROCK as a mediator of TGF-β-dependent tissue stiffening. Moreover, expression analyses suggested that lysyl oxidase (LOX) is a downstream target of the ROCK-actin-MRTF/SRF pathway and inhibition of this pathway by Latrunculin A and CCG-203971 showed similar anti-fibrotic effects in the ECT model as ROCK inhibitors. In line with the collagen crosslinking function of LOX, its inhibition by βaminopropionitrile resulted in reduced ECT stiffness, but let tissue compaction unaffected. Finally, we show that ROCK inhibition also reduced the compaction and stiffness of engineered heart muscle tissues. Our results indicate that pharmacological inhibition of ROCK has a strong anti-fibrotic potential which is in part due to a decrease in the expression of the collagen crosslinking enzyme lysyl oxidase.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Santos

Hartmann

Zimmermann

et al. 2019

Journal of Molecular and Cellular Cardiology

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“…Rho-kinase (ROCK) inhibitors are able to suppress downstream effects of TNFα by decreasing intercellular adhesion molecule 1 (ICAM-1) expression and therefore reducing leukocyte adhesion to endothelial cells [ 179 ]. ROCK inhibitors such as Fasudil have been shown to reduce inflammatory cytokine expression and leukocyte-induced tissue damage to retinal and vascular epithelial cells in in vitro and in vivo studies [ 180 ]. Intravitreal injection of a ROCK inhibitor was also shown to improve photoreceptor function and reduce photoreceptor apoptosis in the RCS rat model of RP [ 181 ].…”

Section: Clinical Trialsmentioning

confidence: 99%

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Newton

Megaw

2020

Genes

145

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Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments. Recent work has therefore focused on the role of apoptotic and non-apoptotic cell death pathways in RP and the various mechanisms that trigger these pathways in degenerating photoreceptors. In particular, several recent studies have begun to elucidate the role of microglia and innate immune response in the progression of RP. Here, we discuss some of the recent progress in understanding mechanisms of rod and cone photoreceptor death in RP and summarise recent clinical trials targeting these pathways.

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“…One month later visual acuity and central macular thickness were measured. The best corrected visual acuity improved on average by 40 %, and the central macular thickness decreased by approximately 20 %, without any adverse complications [80] . These results confirmed findings shown in a previous smaller trial [81].…”

Section: Diabetic Retinopathymentioning

confidence: 88%