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Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema

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Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema cells Review Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema Milagros Mateos-Olivares 1, Luis García-Onrubia 1,2, Fco. Javier Valentín-Bravo 1, Rogelio González-Sarmiento 3,4 , Maribel Lopez-Galvez 1,5,6, J. Carlos Pastor 1,5,6 , Ricardo Usategui-Martín 5,6,* and Salvador Pastor-Idoate 1,5,6,* 1 Department of Ophthalmology, Hospital Clínico Universitario de Valladolid, 47003 Valladolid, Spain; [email protected] (M.M.-O.); [email protected] (L.G.-O.); [email protected] (F.J.V.-B.); [email protected] (M.L.-G.); [email protected] (J.C.P.) 2 Department of Ophthalmology, St Thomas’ Hospital, London SE1 7EH, UK 3 Area of Infectious, Inflammatory and Metabolic Disease, Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; [email protected] 4 Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, 37007 Salamanca, Spain 5 Retina Group, IOBA (Institute of Applied Ophthalmobiology), University of Valladolid, 47002 Valladolid, Spain 6 Cooperative Network for Research in Ophthalmology Oftared, National Institute of Health Carlos III, 28220 Madrid, Spain * Correspondence: [email protected] (R.U.-M.); [email protected] (S.P.-I.); Tel.: +34-983-423-559 Citation: Mateos-Olivares, M.; Abstract: Diabetic macular oedema (DMO) is one of the leading causes of vision loss associated with García-Onrubia, L.; Valentín-Bravo, diabetic retinopathy (DR). New insights in managing this condition have changed the paradigm in its F.J.; González-Sarmiento, R.; treatment, with intravitreal injections of antivascular endothelial growth factor (anti-VEGF) having Lopez-Galvez, M.; Pastor, J.C.; become the standard therapy for DMO worldwide. However, there is no single standard therapy for Usategui-Martín, R.; Pastor-Idoate, S. all patients DMO refractory to anti-VEGF treatment; thus, further investigation is still needed. The key Rho-Kinase Inhibitors for the obstacles in developing suitable therapeutics for refractory DMO lie in its complex pathophysiology; Treatment of Refractory Diabetic therefore, there is an opportunity for further improvements in the progress and applications of new Macular Oedema. Cells 2021, 10, 1683. drugs. Previous studies have indicated that Rho-associated kinase (Rho-kinase/ROCK) is an essential https://doi.org/10.3390/cells10071683 molecule in the pathogenesis of DMO. This is why the Rho/ROCK signalling pathway has been Academic Editor: Michael E. Boulton proposed as a possible target for new treatments. The present review focuses on the recent progress on the possible role of ROCK and its therapeutic potential in DMO. A systematic literature search Received: 17 May 2021 was performed, covering the years 1991 to 2021, using the following keywords: “rho-Associated Accepted: 29 June 2021 Kinas-es”, “Diabetic Retinopathy”, “Macular Edema”, “Ripasudil”, “Fasudil” and “Netarsudil”. Published: 3 July 2021 Better insight into the pathological role of Rho-kinase/ROCK may lead to the development of new strategies for refractory DMO treatment and prevention. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Keywords: diabetic macular oedema; diabetic retinopathy; macular oedema; rho-associated kinases published maps and institutional affil- iations. 1. Introduction Diabetic retinopathy (DR) is one of the feared chronic complications of Diabetes Copyright: © 2021 by the authors. Mellitus (DM), a pandemic disease that affects approximately 463 million adults nowadays. Licensee MDPI, Basel, Switzerland. Its prevalence has been rising in recent years, exemplifying its steady increase; by 2045, This article is an open access article 700 million adults are expected to live with diabetes. A total of 40% of diabetic patients distributed under the terms and over 40 years old suffer from DR. [1]. conditions of the Creative Commons Diabetic macular oedema (DMO) is associated with an abnormal increase in fluid Attribution (CC BY) license (https:// volume in the macula, whether infiltrating retinal layers or collecting in the subretinal creativecommons.org/licenses/by/ space. It is a significant cause of vision loss in those patients since it primarily affects central 4.0/). Cells 2021, 10, 1683. https://doi.org/10.3390/cells10071683 https://www.mdpi.com/journal/cells Cells 2021, 10, 1683 2 of 23 vision. DMO may occur in any disease stage and is more frequent in insulin-dependent type 2 DM [1]. The pathogenesis of DMO is multifactorial and complex, with a combination of pathological conditions related to retinal hypoxia, vascular permeability, angiogenesis, and inflammation processes leading to the development of the characteristic retinal alterations in patients with DMO [2–5]. Since the 1970s, focal/grid laser treatment has been considered the only available treatment for the management of this and it was accepted that in general, it only stabilised functional loss but did not improve it [6]. However, the breakthrough of intravitreal antivascular endothelial growth factor (VEGF) therapy has now replaced laser treatment as several trials have shown improved outcomes [7,8], which is nowadays the treatment of choice. However, anti-VEGF therapy has several limitations since it requires multiple visits and injections, increasing the burden placed on the healthcare system. Furthermore, DMO persists in more than 40% of patients even after numerous intravitreal injections according to the protocol I trial [4]. The efficacy of anti-VEGF treatment may be less pronounced in the clinical practice setting where undertreatment is very frequent [9–11] (Figure1). Cells 2021, 10, x FOR PEER REVIEW Moreover, there are certain doubts about the long-term effect of the3 of inhibition 24 of a factor (VEGF) that is essential, among other things, to keep the choriocapillaris in good condition. Figure 1. 1. RetinalRetinal alterations alterations despite despite sustained sustained intravitreal intravitreal therapy therapy for DMO for.DMO. Color Colorfundus fundus photography photography (a,b), fluorescein angiography (FA) (c,h), and spectral-domain optical coherence tomography (SD-OCT) (i,l) of a patient with nonproliferative diabetic retinopathy and refractory diabetic macular oedema (rDMO). (a,b) Hard exudates (top left and right, white arrows), microaneurysms and retinal hemorrhages (black arrows). (c,d) Early phase of FA showing multiple hyperfluorescent spots predominantly from areas with microaneurysmatic changes (green arrows) and hyperreflectivity of focal laser scars (yellow stars). (e,h) Late-phase of FA of the same patient showing diffuse leakage from microaneurysm (green stars), circinate areas (blue stars) towards and within the foveal avascular zone corresponding to rDMO (red stars). (i,j) SD-OCT displaying multiple intraretinal cysts and subfoveal neuroretinal detachment (white asterisk). (k,l) B-scans of the same patient, 14 years after multiple treatments, showing refractory cystoid macular oedema, multiple hyperreflective dots and disruption of external retinal layers (red arrowheads). Cells 2021, 10, 1683 3 of 23 (A,B), fluorescein angiography (FA) (C,H), and spectral-domain optical coherence tomography (SD- OCT) (I,L) of a patient with nonproliferative diabetic retinopathy and refractory diabetic macular oedema (rDMO). (A,B) Hard exudates (top left and right, white arrows), microaneurysms and retinal hemorrhages (black arrows). (C,D) Early phase of FA showing multiple hyperfluorescent spots predominantly from areas with microaneurysmatic changes (green arrows) and hyperreflectivity of focal laser scars (yellow stars). (E–H) Late-phase of FA of the same patient showing diffuse leakage from microaneurysm (green stars), circinate areas (blue stars) towards and within the foveal avascular zone corresponding to rDMO (red stars). (I,J) SD-OCT displaying multiple intraretinal cysts and subfoveal neuroretinal detachment (white asterisk). (K,L) B-scans of the same patient, 14 years after multiple treatments, showing refractory cystoid macular oedema, multiple hyperreflective dots and disruption of external retinal layers (red arrowheads). 2. Materials and Methods A comprehensive review of the literature was performed through MEDLINE, PubMed, Web of Science, Scopus, and Embase electronic databases, covering the years 1991–2021. Potentially relevant articles were sought by using the search terms in combination as Medi- cal Subject Headings (MeSH) terms and text words: “rho-Associated Kinases”, “Diabetic Retinopathy”, “Diabetic Macular Edema”, “Ripasudil”, “Fasudil” and “Netarsudil”. We also studied reviews, comments, and disquisitions on the pathology. In addition, we scanned the reference lists of the retrieved publications to identify additional relevant articles. The search was supplemented using the MEDLINE option ‘Related Articles’. No language restrictions were applied. The abstracts for each article were studied to ensure relevance and significance to the review. The identification of studies was illustrated using the PRISMA 2020 flow diagram for new systematic reviews (Supplementary File S1). Two reviewers independently rated the quality of each study by assessing its methodology with the Mixed Methods Appraisal Tool (MMAT), designed for the appraisal of the stage of systematic mixed studies reviews (Supplementary File S2) [12]. 3. Pathophysiology of Diabetic Macular Oedema These pathogenic mechanisms of DMO are multifactorial and complex, making its management challenging.
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