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Special Issue "Retinal Degeneration: From Pathophysiology to Therapeutic Approaches"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2019).

Special Issue Editor

Assoc. Prof. Dr. Jan Wijnholds
E-Mail Website
Guest Editor
Department of Ophthalmology, LUMC, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
Interests: retinal degeneration; AAV gene therapy; Crumbs homologue-1; CRB1

Special Issue Information

Dear Colleagues,

Loss of vision due to retinal degeneration can have monogenic or multifactorial causes. There is an urgent search for cures, treatments and prevention for children as well as adults affected by retinitis pigmentosa, age-related macular degeneration, Usher syndrome and other retinal degenerative diseases. A first retinal gene therapy medicine has recently been approved by regulatory agencies and other studies are ongoing in the clinic, but there are many more retinal disease genes without an available medicine. The retina is well accessible through image-guided surgical intervention including gene therapy and the transplantation of retinal cells. Neural retina and retinal pigment epithelium (RPE) can be generated from induced pluripotent stem cells (hiPSC) and used for pre-clinical studies.

This issue of the International Journal of Molecular Sciences will focus on recent insights in “Retinal Degeneration: From Pathophysiology to Therapeutic Approaches”, including new insights into hereditary disease, human and animal retinal pathology due to gene mutations, retinal inflammation, retinal gene therapy, hiPSC-derived neural retina and RPE, natural history studies on patients, pre-and clinical gene therapy, animal models for hereditary retinal dystrophy, retinal imaging, and submissions dealing with these topics are welcome.

Assoc. Prof. Dr. Jan Wijnholds
Guest Editor

Manuscript Submission Information

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Keywords

  • hereditary retinal disease
  • retinal inflammation
  • retinal gene augmentation, editing, optogenetics and splice modulation therapy
  • natural history studies of the retina
  • human iPSC-derived retina and retinal pigment epithelium
  • retinal iPSC-derived cell therapy
  • retinal pathology
  • pre- and clinical gene therapy
  • animal models for retinal dystrophy
  • retinal imaging

Published Papers (12 papers)

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Research

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Open AccessArticle
Mechanisms and Treatment of Light-Induced Retinal Degeneration-Associated Inflammation: Insights from Biochemical Profiling of the Aqueous Humor
Int. J. Mol. Sci. 2020, 21(3), 704; https://doi.org/10.3390/ijms21030704 - 21 Jan 2020
Abstract
Ocular inflammation contributes to the pathogenesis of blind-causing retinal degenerative diseases, such as age-related macular degeneration (AMD) or photic maculopathy. Here, we report on inflammatory mechanisms that are associated with retinal degeneration induced by bright visible light, which were revealed while using a [...] Read more.
Ocular inflammation contributes to the pathogenesis of blind-causing retinal degenerative diseases, such as age-related macular degeneration (AMD) or photic maculopathy. Here, we report on inflammatory mechanisms that are associated with retinal degeneration induced by bright visible light, which were revealed while using a rabbit model. Histologically and electrophysiologically noticeable degeneration of the retina is preceded and accompanied by oxidative stress and inflammation, as evidenced by granulocyte infiltration and edema in this tissue, as well as the upregulation of total protein, pro-inflammatory cytokines, and oxidative stress markers in aqueous humor (AH). Consistently, quantitative lipidomic studies of AH elucidated increase in the concentration of arachidonic (AA) and docosahexaenoic (DHA) acids and lyso-platelet activating factor (lyso-PAF), together with pronounced oxidative and inflammatory alterations in content of lipid mediators oxylipins. These alterations include long-term elevation of prostaglandins, which are synthesized from AA via cyclooxygenase-dependent pathways, as well as a short burst of linoleic acid derivatives that can be produced by both enzymatic and non-enzymatic free radical-dependent mechanisms. The upregulation of all oxylipins is inhibited by the premedication of the eyes while using mitochondria-targeted antioxidant SkQ1, whereas the accumulation of prostaglandins and lyso-PAF can be specifically suppressed by topical treatment with cyclooxygenase inhibitor Nepafenac. Interestingly, the most prominent antioxidant and anti-inflammatory benefits and overall retinal protective effects are achieved by simultaneous administrating of both drugs indicating their synergistic action. Taken together, these findings provide a rationale for using a combination of mitochondria-targeted antioxidant and cyclooxygenase inhibitor for the treatment of inflammatory components of retinal degenerative diseases. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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Open AccessArticle
Degenerated Cones in Cultured Human Retinas Can Successfully Be Optogenetically Reactivated
Int. J. Mol. Sci. 2020, 21(2), 522; https://doi.org/10.3390/ijms21020522 - 14 Jan 2020
Abstract
Biblical references aside, restoring vision to the blind has proven to be a major technical challenge. In recent years, considerable advances have been made towards this end, especially when retinal degeneration underlies the vision loss such as occurs with retinitis pigmentosa. Under these [...] Read more.
Biblical references aside, restoring vision to the blind has proven to be a major technical challenge. In recent years, considerable advances have been made towards this end, especially when retinal degeneration underlies the vision loss such as occurs with retinitis pigmentosa. Under these conditions, optogenetic therapies are a particularly promising line of inquiry where remaining retinal cells are made into “artificial photoreceptors”. However, this strategy is not without its challenges and a model system using human retinal explants would aid its continued development and refinement. Here, we cultured post-mortem human retinas and show that explants remain viable for around 7 days. Within this period, the cones lose their outer segments and thus their light sensitivity but remain electrophysiologically intact, displaying all the major ionic conductances one would expect for a vertebrate cone. We optogenetically restored light responses to these quiescent cones using a lentivirus vector constructed to express enhanced halorhodopsin under the control of the human arrestin promotor. In these ‘reactivated’ retinas, we show a light-induced horizontal cell to cone feedback signal in cones, indicating that transduced cones were able to transmit their light response across the synapse to horizontal cells, which generated a large enough response to send a signal back to the cones. Furthermore, we show ganglion cell light responses, suggesting the cultured explant’s condition is still good enough to support transmission of the transduced cone signal over the intermediate retinal layers to the final retinal output level. Together, these results show that cultured human retinas are an appropriate model system to test optogenetic vision restoration approaches and that cones which have lost their outer segment, a condition occurring during the early stages of retinitis pigmentosa, are appropriate targets for optogenetic vision restoration therapies. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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Open AccessArticle
Autosomal Dominant Retinitis Pigmentosa Due to Class B Rhodopsin Mutations: An Objective Outcome for Future Treatment Trials
Int. J. Mol. Sci. 2019, 20(21), 5344; https://doi.org/10.3390/ijms20215344 - 27 Oct 2019
Abstract
Gene therapy for adRP due to RHO mutations was recently shown to prevent photoreceptor death in a canine model of Class B disease. Among translational steps to be taken, one is to determine a method to detect efficacy in a human clinical trial. [...] Read more.
Gene therapy for adRP due to RHO mutations was recently shown to prevent photoreceptor death in a canine model of Class B disease. Among translational steps to be taken, one is to determine a method to detect efficacy in a human clinical trial. The relatively slow progression of adRP becomes a difficulty for clinical trials requiring an answer to whether there is slowed progression of degeneration in response to therapy. We performed a single-center, retrospective observational study of cross-sectional and longitudinal data. The study was prompted by our identification of a pericentral disease distribution in Class B RHO-adRP. Ultrawide optical coherence tomography (OCT) scans were used. Inferior retinal pericentral defects was an early disease feature. Degeneration further inferior in the retina merged with the pericentral defect, which extended into superior retina. In about 70% of patients, there was an asymmetric island of structure with significantly greater superior than inferior ellipsoid zone (EZ) extent. Serial measures of photoreceptor structure by OCT indicated constriction in superior retinal extent within a two-year interval. We conclude that these results should allow early-phase trials of therapy in RHO-adRP to move forward by inclusion of patients with an asymmetric extent of photoreceptor structure and by monitoring therapeutic effects over two years in the superior retina, a reasonable target for subretinal injection. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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Open AccessArticle
Therapeutic Effect of Garcinia cambogia Extract and Hydroxycitric Acid Inhibiting Hypoxia-Inducible Factor in a Murine Model of Age-Related Macular Degeneration
Int. J. Mol. Sci. 2019, 20(20), 5049; https://doi.org/10.3390/ijms20205049 - 11 Oct 2019
Abstract
Background: Age-related macular degeneration (AMD) is the leading cause of blindness and can be classified into two types called atrophic AMD (dry AMD) and neovascular AMD (wet AMD). Dry AMD is characterized by cellular degeneration of the retinal pigment epithelium, choriocapillaris, and photoreceptors. [...] Read more.
Background: Age-related macular degeneration (AMD) is the leading cause of blindness and can be classified into two types called atrophic AMD (dry AMD) and neovascular AMD (wet AMD). Dry AMD is characterized by cellular degeneration of the retinal pigment epithelium, choriocapillaris, and photoreceptors. Wet AMD is characterized by the invasion of abnormal vessels from the choroid. Although anti-vascular endothelial growth factor (VEGF) therapy has a potent therapeutic effect against the disease, there is a possibility of chorio-retinal atrophy and adverse systemic events due to long-term robust VEGF antagonism. We focused on hypoxia-inducible factor (HIF) regulation of VEGF transcription, and report the suppressive effects of HIF inhibition against ocular phenotypes in animal models. Many of the known HIF inhibitors are categorized as anti-cancer drugs, and their systemic side effects are cause for concern in clinical use. In this study, we explored food ingredients that have HIF inhibitory effects and verified their effects in an animal model of AMD. Methods: Food ingredients were screened using a luciferase assay. C57BL6/J mice were administered the Garcinia cambogia extract (Garcinia extract) and hydroxycitric acid (HCA). Choroidal neovascularization (CNV) was induced by laser irradiation. Results: Garcinia extract and HCA showed inhibitory effects on HIF in the luciferase assay. The laser CNV model mice showed significant reduction of CNV volume by administering Garcinia extract and HCA. Conclusions: Garcinia extract and HCA showed therapeutic effects in a murine AMD model. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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Open AccessArticle
Disruptions of Autophagy in the Rat Retina with Age During the Development of Age-Related-Macular-Degeneration-like Retinopathy
Int. J. Mol. Sci. 2019, 20(19), 4804; https://doi.org/10.3390/ijms20194804 - 27 Sep 2019
Cited by 1
Abstract
Age-related macular degeneration (AMD) is one of the main causes of vision impairment in the elderly. Autophagy is the process of delivery of cytoplasmic components into lysosomes for cleavage; its age-related malfunction may contribute to AMD. Here we showed that the development of [...] Read more.
Age-related macular degeneration (AMD) is one of the main causes of vision impairment in the elderly. Autophagy is the process of delivery of cytoplasmic components into lysosomes for cleavage; its age-related malfunction may contribute to AMD. Here we showed that the development of AMD-like retinopathy in OXYS rats is accompanied by retinal transcriptome changes affecting genes involved in autophagy. These genes are associated with kinase activity, immune processes, and FoxO, mTOR, PI3K-AKT, MAPK, AMPK, and neurotrophin pathways at preclinical and manifestation stages, as well as vesicle transport and processes in lysosomes at the progression stage. We demonstrated a reduced response to autophagy modulation (inhibition or induction) in the OXYS retina at age 16 months: expression of genes Atg5, Atg7, Becn1, Nbr1, Map1lc3b, p62, and Gabarapl1 differed between OXYS and Wistar (control) rats. The impaired reactivity of autophagy was confirmed by a decreased number of autophagosomes under the conditions of blocked autophagosome–lysosomal fusion according to immunohistochemical analysis and transmission electron microscopy. Thus, the development of AMD signs occurs against the background of changes in the expression of autophagy-related genes and a decrease in autophagy reactivity: the ability to enhance autophagic flux in response to stress. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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Open AccessArticle
Cellular Mechanisms of Angiogenesis in Neonatal Rat Models of Retinal Neurodegeneration
Int. J. Mol. Sci. 2019, 20(19), 4759; https://doi.org/10.3390/ijms20194759 - 25 Sep 2019
Abstract
Νeuronal and glial cells play an important role in the development of vasculature in the retina. In this study, we investigated whether re-vascularization occurs in retinal neurodegenerative injury models. To induce retinal injury, N-methyl-D-aspartic acid (NMDA, 200 nmol) or kainic acid (KA, [...] Read more.
Νeuronal and glial cells play an important role in the development of vasculature in the retina. In this study, we investigated whether re-vascularization occurs in retinal neurodegenerative injury models. To induce retinal injury, N-methyl-D-aspartic acid (NMDA, 200 nmol) or kainic acid (KA, 20 nmol) was injected into the vitreous chamber of the eye on postnatal day (P)7. Morphological changes in retinal neurons and vasculature were assessed on P14, P21, and P35. Prevention of vascular growth and regression of some capillaries were observed on P14 in retinas of NMDA- and KA-treated eyes. However, vascular growth and re-vascularization started on P21, and the retinal vascular network was established by P35 in retinas with neurodegenerative injuries. The re-vascularization was suppressed by a two-day treatment with KRN633, an inhibitor of VEGF receptor tyrosine kinase, on P21 and P22. Astrocytes and Müller cells expressed vascular endothelial growth factor (VEGF), and the distribution pattern of VEGF was almost the same between the control and the NMDA-induced retinal neurodegenerative injury model, except for the difference in the thickness of the inner retinal layer. During re-vascularization, angiogenic sprouts from pre-existing blood vessels were present along the network of fibronectins formed by astrocytes. These results suggest that glial cells contribute to angiogenesis in neonatal rat models of retinal neurodegeneration. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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Open AccessArticle
CRB2 Loss in Rod Photoreceptors Is Associated with Progressive Loss of Retinal Contrast Sensitivity
Int. J. Mol. Sci. 2019, 20(17), 4069; https://doi.org/10.3390/ijms20174069 - 21 Aug 2019
Cited by 1
Abstract
Variations in the Crumbs homolog-1 (CRB1) gene are associated with a wide variety of autosomal recessive retinal dystrophies, including early onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). CRB1 belongs to the Crumbs family, which in mammals includes CRB2 and [...] Read more.
Variations in the Crumbs homolog-1 (CRB1) gene are associated with a wide variety of autosomal recessive retinal dystrophies, including early onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). CRB1 belongs to the Crumbs family, which in mammals includes CRB2 and CRB3. Here, we studied the specific roles of CRB2 in rod photoreceptor cells and whether ablation of CRB2 in rods exacerbates the Crb1-disease. Therefore, we assessed the morphological, retinal, and visual functional consequences of specific ablation of CRB2 from rods with or without concomitant loss of CRB1. Our data demonstrated that loss of CRB2 in mature rods resulted in RP. The retina showed gliosis and disruption of the subapical region and adherens junctions at the outer limiting membrane. Rods were lost at the peripheral and central superior retina, while gross retinal lamination was preserved. Rod function as measured by electroretinography was impaired in adult mice. Additional loss of CRB1 exacerbated the retinal phenotype leading to an early reduction of the dark-adapted rod photoreceptor a-wave and reduced contrast sensitivity from 3-months-of-age, as measured by optokinetic tracking reflex (OKT) behavior testing. The data suggest that CRB2 present in rods is required to prevent photoreceptor degeneration and vision loss. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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Open AccessArticle
Evidences Suggesting that Distinct Immunological and Cellular Responses to Light Damage Distinguishes Juvenile and Adult Rat Retinas
Int. J. Mol. Sci. 2019, 20(11), 2744; https://doi.org/10.3390/ijms20112744 - 04 Jun 2019
Abstract
To unravel the mechanisms behind the higher resistance to light damage of juvenile (JR) versus adult (AR) rats, Sprague Dawley rats were exposed to a bright luminous environment of 10, 000 lux. The light-induced retinopathy (LIR) was assessed with histology, electroretinography and immunohistochemistry [...] Read more.
To unravel the mechanisms behind the higher resistance to light damage of juvenile (JR) versus adult (AR) rats, Sprague Dawley rats were exposed to a bright luminous environment of 10, 000 lux. The light-induced retinopathy (LIR) was assessed with histology, electroretinography and immunohistochemistry (IHC). In JR, 2 days of exposure induced the typical LIR, while >3 days added little LIR. IHC revealed a subtle migration of microglia (Iba1 marker) from the inner to the outer retina after 3 days of exposure in JR contrasting with the stronger reaction seen after 1 day in AR. Similarly, in JR, the Müller cells expressed less intense GFAP, CNTF and FGF2 staining compared to AR. Our results suggest that in JR the degree of retinal damage is not proportional to the duration of light exposure (i.e., dose-independent retinopathy), contrasting with the dose-dependent LIR reported in AR. The immature immune system in JR may explain the delayed and/or weaker inflammatory response compared to AR, a finding that would also point to the devastating contribution of the immune system in generating the LIR phenotype, a claim also advanced to explain the pathophysiology of other retinal degenerative disorders such as Age-related Macular Degeneration, Diabetic Retinopathy and Retinitis Pigmentosa. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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Open AccessCommunication
Short-Wavelength Sensitive Cone (S-cone) Testing as an Outcome Measure for NR2E3 Clinical Treatment Trials
Int. J. Mol. Sci. 2019, 20(10), 2497; https://doi.org/10.3390/ijms20102497 - 21 May 2019
Abstract
Recessively-inherited NR2E3 gene mutations cause an unusual retinopathy with abnormally-increased short-wavelength sensitive cone (S-cone) function, in addition to reduced rod and long/middle-wavelength sensitive cone (L/M-cone) function. Progress toward clinical trials to treat patients with this otherwise incurable retinal degeneration prompted the need to [...] Read more.
Recessively-inherited NR2E3 gene mutations cause an unusual retinopathy with abnormally-increased short-wavelength sensitive cone (S-cone) function, in addition to reduced rod and long/middle-wavelength sensitive cone (L/M-cone) function. Progress toward clinical trials to treat patients with this otherwise incurable retinal degeneration prompted the need to determine efficacy outcome measures. Comparisons were made between three computerized perimeters available in the clinic. These perimeters could deliver short-wavelength stimuli on longer-wavelength adapting backgrounds to measure whether S-cone vision can be quantified. Results from a cohort of normal subjects were compared across the three perimeters to determine S-cone isolation and test-retest variability. S-cone perimetry data from NR2E3-ESCS (enhanced S-cone syndrome) patients were examined and determined to have five stages of disease severity. Using these stages, strategies were proposed for monitoring efficacy of either a focal or retina-wide intervention. This work sets the stage for clinical trials. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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Review

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Open AccessReview
RNA editing as a therapeutic approach for retinal gene therapy requiring long coding sequences
Int. J. Mol. Sci. 2020, 21(3), 777; https://doi.org/10.3390/ijms21030777 (registering DOI) - 25 Jan 2020
Abstract
RNA editing aims to treat genetic disease through altering gene expression at the transcript level. Pairing site-directed RNA-targeting mechanisms with engineered deaminase enzymes allows for the programmable correction of G>A and T>C mutations in RNA. This offers a promising therapeutic approach for a [...] Read more.
RNA editing aims to treat genetic disease through altering gene expression at the transcript level. Pairing site-directed RNA-targeting mechanisms with engineered deaminase enzymes allows for the programmable correction of G>A and T>C mutations in RNA. This offers a promising therapeutic approach for a range of genetic diseases. For inherited retinal degenerations caused by point mutations in large genes not amenable to single-adeno-associated viral (AAV) gene therapy such as USH2A and ABCA4, correcting RNA offers an alternative to gene replacement. Genome editing of RNA rather than DNA may offer an improved safety profile, due to the transient and potentially reversible nature of edits made to RNA. This review considers the current site-directing RNA editing systems, and the potential to translate these to the clinic for the treatment of inherited retinal degeneration. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
Open AccessReview
Gene Therapy in Retinal Dystrophies
Int. J. Mol. Sci. 2019, 20(22), 5722; https://doi.org/10.3390/ijms20225722 - 14 Nov 2019
Abstract
Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous degenerative disorders. To date, mutations have been associated with IRDs in over 270 disease genes, but molecular diagnosis still remains elusive in about a third of cases. The methodologic developments in [...] Read more.
Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous degenerative disorders. To date, mutations have been associated with IRDs in over 270 disease genes, but molecular diagnosis still remains elusive in about a third of cases. The methodologic developments in genome sequencing techniques that we have witnessed in this last decade have represented a turning point not only in diagnosis and prognosis but, above all, in the identification of new therapeutic perspectives. The discovery of new disease genes and pathogenetic mechanisms underlying IRDs has laid the groundwork for gene therapy approaches. Several clinical trials are ongoing, and the recent approval of Luxturna, the first gene therapy product for Leber congenital amaurosis, marks the beginning of a new era. Due to its anatomical and functional characteristics, the retina is the organ of choice for gene therapy, although there are quite a few difficulties in the translational approaches from preclinical models to humans. In the first part of this review, an overview of the current knowledge on methodological issues and future perspectives of gene therapy applied to IRDs is discussed; in the second part, the state of the art of clinical trials on the gene therapy approach in IRDs is illustrated. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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Open AccessReview
Proteomic Biomarkers of Retinal Inflammation in Diabetic Retinopathy
Int. J. Mol. Sci. 2019, 20(19), 4755; https://doi.org/10.3390/ijms20194755 - 25 Sep 2019
Abstract
Diabetic retinopathy (DR), a sight-threatening neurovasculopathy, is the leading cause of irreversible blindness in the developed world. DR arises as the result of prolonged hyperglycemia and is characterized by leaky retinal vasculature, retinal ischemia, retinal inflammation, angiogenesis, and neovascularization. The number of DR [...] Read more.
Diabetic retinopathy (DR), a sight-threatening neurovasculopathy, is the leading cause of irreversible blindness in the developed world. DR arises as the result of prolonged hyperglycemia and is characterized by leaky retinal vasculature, retinal ischemia, retinal inflammation, angiogenesis, and neovascularization. The number of DR patients is growing with an increase in the elderly population, and therapeutic approaches are limited, therefore, new therapies to prevent retinal injury and enhance repair are a critical unmet need. Besides vascular endothelial growth factor (VEGF)-induced vascular proliferation, several other mechanisms are important in the pathogenesis of diabetic retinopathy, including vascular inflammation. Thus, combining anti-VEGF therapy with other new therapies targeting these pathophysiological pathways of DR may further optimize treatment outcomes. Technological advancements have allowed for high-throughput proteomic studies examining biofluids such as aqueous humor, vitreous humor, tear, and serum. Many DR biomarkers have been identified, especially proteins involved in retinal inflammatory processes. This review attempts to summarize the proteomic biomarkers of DR-associated retinal inflammation identified over the last several years. Full article
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
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