Current and Future Treatments for Diabetic Retinopathy

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (1 June 2021) | Viewed by 21760

Special Issue Editors


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Guest Editor
1. Eyevensys, 11 Rue Watt, 75013 Paris, France
2. Centre de Recherche des Cordeliers, INSERM, Université de Paris Cité, Sorbonne Université, From Physiopathology of Ocular Diseases to Clinical Development, 75006 Paris, France
3. Cochin Hospital, AP-HP, Assistance Publique Hôpitaux de Paris, 24 rue du Faubourg Saint Jacques, 75014 Paris, France
Interests: neuroprotection; diabetic retinopathy; retinal ischemia; glia; drug development
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Co-Guest Editor
Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel
Interests: retina; retinal imaging; diabetic retinopathy; surgical retina; cell therapy

Special Issue Information

Dear Colleagues,

Diabetic retinopathy remains the first cause of blindness in the younger and active population, despite the major recent advances achieved in the reduction of diabetic macular edema (DME). In fact, many aspects of diabetic retinopathy are not targeted by anti-VEGF therapy or by corticosteroids, and vision gain still remains limited for many patients.

New molecular targets have been identified in diabetic retinopathy pathogenesis, which are involved in ischemia, neuronal cell death, glial metabolism, or vasculopathy, and old drugs as well as new drug candidates targeting these pathways have been discovered and evaluated in animal models.

In this Special Issue, we will summarize the benefits of the treatments currently available for DME and present potential new drug candidates for this devastating disease.

Prof. Francine Behar-Cohen
Prof. Dr. Anat Lowenstein
Guest Editor

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Keywords

  • neuroprotection
  • diabetic retinopathy
  • retinal ischemia
  • glia
  • drug targeting
  • drug development

Published Papers (8 papers)

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Editorial

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3 pages, 196 KiB  
Editorial
Current and Future Treatments for Diabetic Retinopathy
by Francine Behar-Cohen and Anat Loewenstein
Pharmaceutics 2022, 14(4), 812; https://doi.org/10.3390/pharmaceutics14040812 - 07 Apr 2022
Cited by 1 | Viewed by 1567
Abstract
The pathogenesis of diabetic retinopathy in humans remains imperfectly understood; in particular, the kinetics of the various pathogenic events in the very early stages of retinal damage are difficult to recognize [...] Full article
(This article belongs to the Special Issue Current and Future Treatments for Diabetic Retinopathy)

Research

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14 pages, 1938 KiB  
Article
Tauroursodeoxycholic Acid Protects Retinal and Visual Function in a Mouse Model of Type 1 Diabetes
by Jieming Fu, Moe H. Aung, Megan C. Prunty, Adam M. Hanif, Lauren M. Hutson, Jeffrey H. Boatright and Machelle T. Pardue
Pharmaceutics 2021, 13(8), 1154; https://doi.org/10.3390/pharmaceutics13081154 - 27 Jul 2021
Cited by 13 | Viewed by 1805
Abstract
Purpose: Previous studies demonstrated that systemic treatment with tauroursodeoxycholic acid (TUDCA) is protective in in vivo mouse models of retinal degeneration and in culture models of hyperglycemia. This study tested the hypothesis that TUDCA will preserve visual and retinal function in a mouse [...] Read more.
Purpose: Previous studies demonstrated that systemic treatment with tauroursodeoxycholic acid (TUDCA) is protective in in vivo mouse models of retinal degeneration and in culture models of hyperglycemia. This study tested the hypothesis that TUDCA will preserve visual and retinal function in a mouse model of early diabetic retinopathy (DR). Methods: Adult C57BL/6J mice were treated with streptozotocin (STZ) and made diabetic at 8–10 weeks of age. Control and diabetic mice were treated with vehicle or TUDCA starting 1 or 3 weeks after induction of diabetes, and were assessed bimonthly for visual function via an optomotor response and monthly for retinal function via scotopic electroretinograms. Results: Diabetic mice showed significantly reduced spatial frequency and contrast sensitivity thresholds compared to control mice, while diabetic mice treated early with TUDCA showed preservation at all timepoints. A-wave, b-wave, and oscillatory potential 2 (OP2) amplitudes decreased in diabetic mice. Diabetic mice also exhibited delays in a-wave and OP2-implicit times. Early TUDCA treatment ameliorated a-wave, b-wave, and OP2 deficits. Late TUDCA treatment showed reduced preservation effects compared to early treatment. Conclusions: Early TUDCA treatment preserved visual function in an STZ-mouse model of Type I diabetes. These data add to a growing body of preclinical research that may support testing whether TUDCA may be an effective early clinical intervention against declining visual function caused by diabetic retinopathy. Full article
(This article belongs to the Special Issue Current and Future Treatments for Diabetic Retinopathy)
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17 pages, 4032 KiB  
Article
Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy
by Cecile Lebon, Heike Neubauer, Marianne Berdugo, Kimberley Delaunay, Elke Markert, Kolja Becker, Katja S. Baum-Kroker, Jürgen Prestle, Holger Fuchs, Remko A. Bakker and Francine Behar-Cohen
Pharmaceutics 2021, 13(8), 1105; https://doi.org/10.3390/pharmaceutics13081105 - 21 Jul 2021
Cited by 3 | Viewed by 2611
Abstract
Rho-associated kinase (ROCK) activation was shown to contribute to microvascular closure, retinal hypoxia, and to retinal pigment epithelium (RPE) barrier disruption in a rat model of diabetic retinopathy. Fasudil, a clinically approved ROCK inhibitor, improved retinal perfusion and reduced edema in this model, [...] Read more.
Rho-associated kinase (ROCK) activation was shown to contribute to microvascular closure, retinal hypoxia, and to retinal pigment epithelium (RPE) barrier disruption in a rat model of diabetic retinopathy. Fasudil, a clinically approved ROCK inhibitor, improved retinal perfusion and reduced edema in this model, indicating that ROCK inhibition could be a promising new therapeutic approach for the treatment of diabetic retinopathy. However, due to its short intravitreal half-life, fasudil is not suitable for long-term treatment. In this study, we evaluated a very potent ROCK1/2 inhibitor (BIRKI) in a depot formulation administered as a single intravitreal injection providing a slow release for at least four weeks. Following BIRKI intravitreal injection in old Goto-Kakizaki (GK) type 2 diabetic rats, we observed a significant reduction in ROCK1 activity in the retinal pigment epithelium/choroid complex after 8 days and relocation of ROCK1 to the cytoplasm and nucleus in retinal pigment epithelium cells after 28 days. The chronic ROCK inhibition by the BIRKI depot formulation restored retinal pigment epithelial cell morphology and distribution, favored retinal capillaries dilation, and reduced hypoxia and inner blood barrier leakage observed in the diabetic retina. No functional or morphological negative effects were observed, indicating suitable tolerability of BIRKI after intravitreous injection. In conclusion, our data suggest that sustained ROCK inhibition, provided by BIRKI slow-release formulation, could be a valuable treatment option for diabetic retinopathy, especially with regard to the improvement of retinal vascular infusion and protection of the outer retinal barrier. Full article
(This article belongs to the Special Issue Current and Future Treatments for Diabetic Retinopathy)
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16 pages, 2728 KiB  
Article
Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model
by Marianne Berdugo, Kimberley Delaunay, Cécile Lebon, Marie-Christine Naud, Lolita Radet, Léa Zennaro, Emilie Picard, Alejandra Daruich, Jacques Beltrand, Elsa Kermorvant-Duchemin, Michel Polak, Patricia Crisanti and Francine F. Behar-Cohen
Pharmaceutics 2021, 13(7), 1095; https://doi.org/10.3390/pharmaceutics13071095 - 17 Jul 2021
Cited by 14 | Viewed by 2382
Abstract
Diabetic retinopathy (DR) remains a major cause of vision loss, due to macular edema, retinal ischemia and death of retinal neurons. We previously demonstrated that acute administration of glibenclamide into the vitreous, or given orally at a non-hypoglycemic dose, protected the structure and [...] Read more.
Diabetic retinopathy (DR) remains a major cause of vision loss, due to macular edema, retinal ischemia and death of retinal neurons. We previously demonstrated that acute administration of glibenclamide into the vitreous, or given orally at a non-hypoglycemic dose, protected the structure and the function of the retina in three animal models that each mimic aspects of diabetic retinopathy in humans. In this pilot study, we investigated whether one year of chronic oral glibenclamide, in a non-hypoglycemic regimen (Amglidia®, 0.4 mg/kg, Ammtek/Nordic Pharma, 5 d/week), could alleviate the retinopathy that develops in the Goto-Kakizaki (GK) rat. In vivo, retinal function was assessed by electroretinography (ERG), retinal thickness by optical coherence tomography (OCT) and retinal perfusion by fluorescein and indocyanin green angiographies. The integrity of the retinal pigment epithelium (RPE) that constitutes the outer retinal barrier was evaluated by quantitative analysis of the RPE morphology on flat-mounted fundus ex vivo. Oral glibenclamide did not significantly reduce the Hb1Ac levels but still improved retinal function, as witnessed by the reduction in scotopic implicit times, limited diabetes-induced neuroretinal thickening and the extension of ischemic areas, and it improved the capillary coverage. These results indicate that low doses of oral glibenclamide could still be beneficial for the prevention of type 2 diabetic retinopathy. Whether the retinas ofpatients treated specifically with glibenclamideare less at risk of developing diabetic complications remains to be demonstrated. Full article
(This article belongs to the Special Issue Current and Future Treatments for Diabetic Retinopathy)
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12 pages, 7958 KiB  
Article
Visual Acuity Gain Profiles and Anatomical Prognosis Factors in Patients with Drug-Naive Diabetic Macular Edema Treated with Dexamethasone Implant: The NAVEDEX Study
by Mauricio Pinto, Thibaud Mathis, Pascale Massin, Jad Akesbi, Théo Lereuil, Nicolas Voirin, Frédéric Matonti, Franck Fajnkuchen, John Conrath, Solange Milazzo, Jean-François Korobelnik, Stéphanie Baillif, Philippe Denis, Catherine Creuzot-Garcher, Mayer Srour, Bénédicte Dupas, Aditya Sudhalkar, Alper Bilgic, Ramin Tadayoni, Eric H Souied, Corinne Dot and Laurent Kodjikianadd Show full author list remove Hide full author list
Pharmaceutics 2021, 13(2), 194; https://doi.org/10.3390/pharmaceutics13020194 - 01 Feb 2021
Cited by 6 | Viewed by 2152
Abstract
The purpose of this study is to evaluate the visual acuity (VA) gain profiles between patients with drug-naive diabetic macular edema (DME) treated by dexamethasone implant (DEX-implant) and assess the baseline anatomical and functional factors that could influence the response to the treatment [...] Read more.
The purpose of this study is to evaluate the visual acuity (VA) gain profiles between patients with drug-naive diabetic macular edema (DME) treated by dexamethasone implant (DEX-implant) and assess the baseline anatomical and functional factors that could influence the response to the treatment in real-life conditions. A retrospective, multi-center observational study included 129 eyes with drug-naive DME treated by DEX-implant. The Median follow-up was 13 months. Two groups of VA gain trajectories were identified—Group A, with 71% (n = 96) of patients whose average VA gain was less than five letters and Group B, with 29% (n = 33) of patients with an average gain of 20 letters. The probability of belonging to Group B was significantly higher in patients with baseline VA < 37 letters (p = 0.001). Ellipsoid zone alterations (EZAs) or disorganization of retinal inner layers (DRILs) were associated with a lower final VA (53.0 letters versus 66.4, p = 0.002) but without a significant difference in VA gain (4.9 letters versus 6.8, p = 0.582). Despite a low baseline VA, this subgroup of patients tends to have greater visual gain, encouraging treatment with DEX-implant in such advanced-stage disease. However, some baseline anatomic parameters, such as the presence of EZAs or DRILs, negatively influenced final vision. Full article
(This article belongs to the Special Issue Current and Future Treatments for Diabetic Retinopathy)
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Review

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22 pages, 1584 KiB  
Review
Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy
by Rafael Simó, Olga Simó-Servat, Patricia Bogdanov and Cristina Hernández
Pharmaceutics 2021, 13(8), 1320; https://doi.org/10.3390/pharmaceutics13081320 - 23 Aug 2021
Cited by 31 | Viewed by 4268
Abstract
The concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages [...] Read more.
The concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages of the disease. However, neurodegeneration is not always the apparent primary event in the natural story of diabetic retinopathy, and a phenotyping characterization is recommendable to identify those patients in whom neuroprotective treatment might be of benefit. In recent years, a myriad of treatments based on neuroprotection have been tested in experimental models, but more interestingly, there are drugs with a dual activity (neuroprotective and vasculotropic). In this review, the recent evidence concerning the therapeutic approaches targeting neurovascular unit impairment will be presented, along with a critical review of the scientific gaps and problems which remain to be overcome before our knowledge can be transferred to clinical practice. Full article
(This article belongs to the Special Issue Current and Future Treatments for Diabetic Retinopathy)
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19 pages, 3633 KiB  
Review
Intravitreal Anti-Vascular Endothelial Growth Factor Agents for the Treatment of Diabetic Retinopathy: A Review of the Literature
by Irini Chatziralli and Anat Loewenstein
Pharmaceutics 2021, 13(8), 1137; https://doi.org/10.3390/pharmaceutics13081137 - 26 Jul 2021
Cited by 28 | Viewed by 3212
Abstract
Background: Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population. The purpose of this review is to gather the existing literature regarding the use of the approved anti-vascular endothelial growth (anti-VEGF) agents in the treatment of DR. Methods: A [...] Read more.
Background: Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population. The purpose of this review is to gather the existing literature regarding the use of the approved anti-vascular endothelial growth (anti-VEGF) agents in the treatment of DR. Methods: A comprehensive literature review in PubMed engine search was performed for articles written in English language up to 1 July 2021, using the keywords “diabetic retinopathy”, “ranibizumab”, “aflibercept”, and “anti-VEGF”. Emphasis was given on pivotal trials and recent robust studies. Results: Intravitreal anti-VEGF agents have been found to significantly improve visual acuity and reduce retinal thickness in patients with diabetic macular edema (DME) in a long-term follow-up ranging from 1 to 5 years and are considered the standard-of-care in such patients. Regarding DR, intravitreal anti-VEGF agents provided ≥2-step improvement in DR severity on color fundus photography in about 30–35% of patients with NPDR at baseline, in the majority of clinical trials originally designed to evaluate the efficacy of intravitreal anti-VEGF agents in patients with DME. Protocol S and CLARITY study have firstly reported that intravitreal anti-VEGF agents are non-inferior to panretinal photocoagulation (PRP) in patients with proliferative DR (PDR). However, the use of new imaging modalities, such as optical coherence tomography-angiography and wide-field fluorescein angiography, reveals conflicting results about the impact of anti-VEGF agents on the regression of retinal non-perfusion in patients with DR. Furthermore, one should consider the high “loss to follow-up” rate and its devastating consequences especially in patients with PDR, when deciding to treat the latter with intravitreal anti-VEGF agents alone compared to PRP. In patients with PDR, combination of treatment of intravitreal anti-VEGF agents and PRP has been also supported. Moreover, in the specific case of vitreous hemorrhage or tractional retinal detachment as complications of PDR, intravitreal anti-VEGF agents have been found to be beneficial as an adjunct to pars plana vitrectomy (PPV), most commonly given 3–7 days before PPV, offering reduction in the recurrence of vitreous hemorrhage. Conclusions: There is no general consensus regarding the use of intravitreal anti-VEGF agents in patients with DR. Although anti-VEGF agents are the gold standard in the treatment of DME and seem to improve DR severity, challenges in their use exist and should be taken into account in the decision of treatment, based on an individualized approach. Full article
(This article belongs to the Special Issue Current and Future Treatments for Diabetic Retinopathy)
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14 pages, 2705 KiB  
Review
Real-World Efficacy and Safety of Fluocinolone Acetonide Implant for Diabetic Macular Edema: A Systematic Review
by Laurent Kodjikian, Stephanie Baillif, Catherine Creuzot-Garcher, Marie-Noëlle Delyfer, Frédéric Matonti, Michel Weber and Thibaud Mathis
Pharmaceutics 2021, 13(1), 72; https://doi.org/10.3390/pharmaceutics13010072 - 07 Jan 2021
Cited by 15 | Viewed by 2679
Abstract
To assess real-world outcomes of fluocinolone acetonide (FAc) implant in treating diabetic macular edema (DME), a systematic literature review was conducted on PubMed in order to identify publications assessing the efficacy and safety of the FAc implant in DME in daily practice. Case [...] Read more.
To assess real-world outcomes of fluocinolone acetonide (FAc) implant in treating diabetic macular edema (DME), a systematic literature review was conducted on PubMed in order to identify publications assessing the efficacy and safety of the FAc implant in DME in daily practice. Case reports and randomized controlled trials were excluded. Twenty-two observational real-world studies analyzing a total of 1880 eyes were included. Mean peak visual gain was +8.7 letters (11.3 months post-FAc injection) and was greater for lower baseline best corrected visual acuity (BCVA) and for more recent DME. Mean central retinal thickness (CRT) decreased 34.3% from baseline. 77.0% of the analyzed studies reported both BCVA improvement of at least five letters and a CRT decrease by 20% or more. Rescue therapy was needed more frequently when FAc was administered for chronic DME. FAc-induced ocular hypertension was reported in 20.1% of patients but only 0.6% needed surgery. Cataract extraction was performed in 43.2% of phakic patients. Adequate patient selection is essential for optimal FAc response and better safety profile. Currently positioned as second- or third-line treatment in the management algorithm, FAc implant decreases treatment burden and provides better letter gain when administered for more recent DME. Full article
(This article belongs to the Special Issue Current and Future Treatments for Diabetic Retinopathy)
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