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Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy.

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, 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.

SUBMITTER: Lebon C

PROVIDER: S-EPMC8401380 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDiabetic retinopathy is a leading cause of visual loss in the working population. Pars plana vitrectomy has become the mainstream treatment option for severe proliferative diabetic retinopathy (PDR) associated with significant vitreous haemorrhage and/or tractional retinal detachment. Despite the advances in surgical equipment, diabetic vitrectomy remains a challenging operation, requiring advanced microsurgical skills, especially in the presence of tractional retinal detachment. Preoperative intravitreal bevacizumab has been widely employed as an adjuvant to ease surgical difficulty and improve postoperative prognosis.Aims: This study aims to assess the effectiveness of preoperative intravitreal bevacizumab in reducing intraoperative complications and improving postoperative outcomes in patients undergoing vitrectomy for the complications of PDR.MethodsA literature search was conducted using the PubMed, Cochrane, and ClinicalTrials.gov databases to identify all related studies published before 31/10/2020. Prespecified outcome measures were operation time, intraoperative iatrogenic retinal breaks, best-corrected visual acuity in the last follow-up visit, the presence of any postoperative vitreous haemorrhage and the need to re-operate. Evidence synthesis was performed using Fixed or Random Effects models, depending on the heterogeneity of the included studies. Heterogeneity was assessed using Q-statistic and I2. Additional meta-regression models, subgroup analyses and sensitivity analyses were performed as appropriate.ResultsThirteen randomized control trials, with a total of 688 eyes were included in this review. Comparison of the intraoperative data showed that bevacizumab reduced operation time (p < 0.001), minimized iatrogenic retinal breaks (p < 0.001), provided better long-term visual acuity outcomes (p = 0.005), and prevented vitreous haemorrhage (p < 0.001) and the need for reoperation (p = 0.001 < 0.05). Findings were strongly corroborated by additional sensitivity and subgroup analyses.ConclusionPreoperative administration of bevacizumab is effective in reducing intraoperative complications and improving the postoperative prognosis of diabetic vitrectomy.PROSPERO registration number: CRD42021219280.

Project description:ImportanceProactive treatment of nonproliferative diabetic retinopathy (NPDR) reduces the risk of progression to vision-threatening complications.ObjectiveTo evaluate vascular endothelial growth factor blockade therapy with intravitreal aflibercept injections in eyes with severe NPDR without diabetic macular edema (DME).Design, setting, and participantsThe Study of the Efficacy and Safety of Intravitreal Aflibercept for the Improvement of Moderately Severe to Severe Nonproliferative Diabetic Retinopathy (PANORAMA) was a double-masked 100-week randomized clinical trial conducted in multiple centers worldwide. The study included 402 adults with Diabetic Retinopathy Severity Scale (DRSS) level 47 or 53 with no DME and best-corrected visual acuity of 20/40 or better.InterventionsIntravitreal injections of aflibercept, 2 mg, every 16 weeks after 3 initial monthly doses and one 8-week interval (aflibercept 2q16 group); intravitreal injections of aflibercept, 2 mg, every 8 weeks after 5 initial monthly doses, with pro re nata (PRN) dosing beginning at week 56 (aflibercept 2q8/PRN group); or sham injections (control group).Main outcomes and measuresProportions of eyes with a 2-step or greater improvement in DRSS level, vision-threatening complications, and center-involved DME from baseline to weeks 24, 52, and 100.ResultsAmong 402 participants (1 eye per participant), the mean (SD) age was 55.7 (10.5) years; 225 (56.0%) were male, and 310 (77.1%) were White. A total of 135 were randomized to the aflibercept 2q16 group, 134 to the aflibercept 2q8/PRN group, and 133 to the control group. At 24 weeks, treatment with aflibercept resulted in a 2-step or greater improvement in DRSS level in 157 of 269 eyes (58.4%) in the combined aflibercept groups vs 8 of 133 eyes (6.0%) in the control group (adjusted difference, 52.3%; 95% CI, 45.2%-59.5%; P < .001). At 52 weeks, 88 of 135 eyes (65.2%) in the aflibercept 2q16 group (adjusted difference, 50.1%; 95% CI, 40.1%-60.1%) and 107 of 134 eyes (79.9%) in the aflibercept 2q8/PRN group (adjusted difference, 64.8%; 95% CI, 55.8%-73.9%) compared with 20 of 133 eyes (15.0%) in the control group (P < .001 for both comparisons) showed a 2-step or greater improvement in DRSS level. Fewer eyes treated with aflibercept vs sham injections developed vision-threatening complications and/or center-involved DME through week 100 (22 of 135 eyes [16.3%] in the 2q16 group [adjusted difference, -34.2%; 95% CI, -44.6 to -23.8] and 25 of 134 eyes [18.7%] in the 2q8/PRN group [adjusted difference, -31.7%; 95% CI, -42.5 to -20.9] compared with 67 of 133 eyes [50.4%] in the control group; P < .001 for both comparisons). No new safety signals were identified.Conclusions and relevanceIn this study, significantly more eyes with moderately severe to severe NPDR that were treated with aflibercept showed a 2-step or greater improvement in DRSS level at 24, 52, and 100 weeks, and significantly fewer eyes treated with aflibercept vs sham developed vision-threatening complications and center-involved DME. Outcomes on the DRSS between year 1 and 2 emphasize the need for ongoing vascular endothelial growth factor suppression and adherence.Trial registrationClinicalTrials.gov Identifier: NCT02718326.

Project description:PurposeIntravitreal anti-VEGF injection (IVI) is administered before vitrectomy to assist management of proliferative diabetic retinopathy (PDR)-related complications. In the clinical setting, retinal surgeons determine the use of preoperative IVI based on individual criteria. In this study, we investigated factors related to the potential bias of retinal surgeons in using IVI prior to vitrectomy for PDR-related complications, and evaluated the real-world outcomes of surgeon-determined preoperative IVI.MethodsMedical records of 409 eyes of 409 patients who underwent 25-gauge vitrectomy for PDR complications at seven Japanese centers (22 surgeons) were retrospectively reviewed. Ocular factors, demographic and general clinical factors, surgical procedures, and postoperative complications were compared between IVI group (patients who received preoperative IVI; 87 eyes, 21.3%) and non-IVI group (patients who did not receive preoperative IVI; 322 eyes, 78.7%). In addition, baseline HbA1c in IVI group and non-IVI group was compared between eyes with and without postoperative complications.ResultsAt baseline, IVI group was younger (P<0.001), had shorter duration of diabetes treatment (P = 0.045), and higher frequencies of neovascular glaucoma [NVG] (P<0.001) and tractional retinal detachment [TRD] (P<0.001) compared to non-IVI group. Although IVI group had higher frequencies of intraoperative retinal break and tamponade procedure, there were no significant differences in postoperative complications and additional treatments between two groups. Baseline HbA1c levels were also not correlated with postoperative complications of VH, NVG, and RD both in IVI group and non-IVI group. Logistic regression analysis identified age (P<0.001, odds ratio [OR] 0.95), presence of NVG (P<0.001, OR 20.2), and presence of TRD (P = 0.0014, OR 2.44) as preoperative factors in favor of IVI.ConclusionsIn this multicenter real-world clinical study, younger age and presence of NVG and TRD were identified as potential biases in using IVI before vitrectomy for PDR complications. Eyes that received preoperative IVI had more intraoperative retinal breaks requiring tamponade than eyes not receiving IVI, but postoperative outcome was not different between the two groups.

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Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy.

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