Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy.
ABSTRACT: Proliferative diabetic retinopathy (PDR), neovascular age-related macular degeneration (nvAMD), retinopathy of prematurity (ROP) and other eye diseases are characterized by retinal and/or choroidal neovascularization, ultimately causing vision loss in millions of people worldwide. nvAMD and PDR are associated with aging and the number of those affected is expected to increase as the global median age and life expectancy continue to rise. With this increase in prevalence, the development of novel, orally bioavailable therapies for neovascular eye diseases that target multiple pathways is critical, since current anti-vascular endothelial growth factor (VEGF) treatments, delivered by intravitreal injection, are accompanied with tachyphylaxis, a high treatment burden and risk of complications. One potential target is apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1). The multifunctional protein APE1/Ref-1 may be targeted via inhibitors of its redox-regulating transcription factor activation activity to modulate angiogenesis, inflammation, oxidative stress response and cell cycle in neovascular eye disease; these inhibitors also have neuroprotective effects in other tissues. An APE1/Ref-1 small molecule inhibitor is already in clinical trials for cancer, PDR and diabetic macular edema. Efforts to develop further inhibitors are underway. APE1/Ref-1 is a novel candidate for therapeutically targeting neovascular eye diseases and alleviating the burden associated with anti-VEGF intravitreal injections.
Project description:Leucine-rich a-2-glycoprotein 1 (LRG1) is a candidate therapeutic target for treating the neovascular form of age-related macular degeneration (nvAMD). In this study we examined the expression of LRG1 in eyes of nvAMD patients. Choroidal neovascular membranes (CNVMs) from patients who underwent submacular surgery for retinal pigment epithelium-choroid graft transplantation were collected from 5 nvAMD patients without any prior intravitreal anti-VEGF injection, and from six patients who received intravitreal anti-VEGF injections before surgery. As controls free of nvAMD, retina sections were obtained from the eyes resected from a patient with lacrimal sac tumor and from a patient with neuroblastoma. CNVMs were immunostained for CD34, LRG1, and α-smooth muscle actin (α-SMA). Aqueous humor samples were collected from 58 untreated-naïve nvAMD patients prior to the intravitreal injection of anti-VEGF and 51 age-matched cataract control patients, and LRG1 concentration was measured by ELISA. The level of LRG1 immunostaining is frequently high in both the endothelial cells of the blood vessels, and myofibroblasts in the surrounding tissue of CNVMs of treatment-naïve nvAMD patients. Furthermore, the average concentration of LRG1 was significantly higher in the aqueous humor of nvAMD patients than in controls. These observations provide a strong experimental basis and scientific rationale for the progression of a therapeutic anti-LRG1 monoclonal antibody into clinical trials with patients with nvAMD.
Project description:The standard care for proliferative diabetic retinopathy (PDR) usually is panretinal photocoagulation, an inherently destructive treatment that can cause iatrogenic vision loss. Therefore, evaluating the effects of therapies for diabetic macular edema on development or worsening of PDR might lead to new therapies for PDR.To evaluate the effects of intravitreal ranibizumab or triamcinolone acetonide, administered to treat diabetic macular edema, on worsening of diabetic retinopathy.Exploratory analysis was performed on worsening of retinopathy, defined as 1 or more of the following: (1) worsening from no PDR to PDR, (2) worsening of 2 or more severity levels on reading center assessment of fundus photographs in eyes without PDR at baseline, (3) having panretinal photocoagulation, (4) experiencing vitreous hemorrhage, or (5) undergoing vitrectomy for the treatment of PDR.Community- and university-based ophthalmology practices.Individuals with central-involved diabetic macular edema causing visual acuity impairment.Eyes were assigned randomly to sham with prompt focal/grid laser, 0.5 mg of intravitreal ranibizumab with prompt or deferred (?24 weeks) laser, or 4 mg of intravitreal triamcinolone acetonide with prompt laser.Three-year cumulative probabilities for retinopathy worsening.For eyes without PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening (P value comparison with sham with prompt laser) were 23% using sham with prompt laser, 18% with ranibizumab with prompt laser (P = .25), 7% with ranibizumab with deferred laser (P = .001), and 37% with triamcinolone with prompt laser (P = .10). For eyes with PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening were 40%, 21% (P = .05), 18% (P = .02), and 12% (P < .001), respectively. CONCLUSIONS AND RELEVANCE Intravitreal ranibizumab appears to be associated with a reduced risk of diabetic retinopathy worsening in eyes with or without PDR. Intravitreal triamcinolone also appears to be associated with a reduced risk of PDR worsening. These findings suggest that use of these drugs to prevent worsening of diabetic retinopathy may be feasible. Given the exploratory nature of these analyses, the risk of endophthalmitis following intravitreal injections, and the fact that intravitreal triamcinolone can cause cataract or glaucoma, use of these treatments to reduce the rates of worsening of retinopathy, with or without PDR, does not seem warranted at this time.
Project description:<h4>Purpose</h4>To assess the impact of COVID-19-related delay in intravitreal injection timing on macular structure and visual acuity (VA) among patients treated for neovascular age-related macular degeneration (nvAMD).<h4>Methods</h4>We reviewed demographic and clinical data and macular ocular computerized tomographic images of 34 patients (48 eyes, group A) who did not follow their injection schedule during the first wave of COVID-19 and compared them to 46 patients (71 eyes, group B) who did. Functional worsening was defined as a loss of at least 0.1 in decimal VA. Anatomic worsening was defined as new or increased subretinal/intraretinal fluids or new hemorrhage.<h4>Results</h4>The planned mean ± standard deviation intervals between the intravitreal injections were 5.7 ± 2.7 weeks for group A and 5.5 ± 2.4 weeks for group B (P = 0.60). The actual intervals were 13.6 ± 6.8 (7.9 ± 5.2 weeks' delay) and 5.3 ± 2.4 weeks (no delay), respectively (P < 0.001). The best corrected visual acuity worsened in 23 group A eyes (47.9%) and in 6 group B eyes (8.5%) (odds ratio [OR] 9.97, P < 0.001). Anatomic features indicative of nvAMD worsening were detected in 31 group A eyes (64.6%) and in 16 group B eyes (22.5%) (OR 5.73, P < 0.001). A new macular hemorrhage was observed in 4 group A eyes (8.3%) and in no group B eyes (P = 0.09).<h4>Conclusion</h4>Delay in timely retinal care during the COVID-19 restrictions period resulted in short-term negative outcomes, including macular bleeding, in nvAMD patients.
Project description:Anti-vascular endothelial growth factors (anti-VEGF) have become the most common treatment modality for many retinal diseases. These include neovascular age-related macular degeneration (n-AMD), proliferative diabetic retinopathy (PDR) and retinal vein occlusions (RVO). However, these drugs are administered via intravitreal injections that are associated with sight-threatening complications. The most feared of these complications is endophthalmitis, a severe infection of the eye with extremely poor visual outcomes. Patients with retinal diseases typically have to undergo multiple injections before achieving the desired therapeutic effect. Each injection incurs the risk of the sight-threatening complications. As such, there has been great interest in developing sustained delivery platforms for anti-VEGF agents to the posterior segment of the eye. In recent years, there have been various strategies that have been conceptualised. These include non-biodegradable implants, nano-formulations and hydrogels. In this review, the barriers of drug delivery to the posterior segment of the eye will be explained. The characteristics of an ideal sustained delivery platform will then be discussed. Finally, the current available strategies will be analysed with the above-mentioned characteristics in mind to determine the advantages and disadvantages of each sustained drug delivery modality. Through the above, this review attempts to provide an overview of the sustained delivery platforms in their various phases of development.
Project description:Apurinic/apyrimidinic (AP) endonuclease-reduction/oxidation factor 1 (APE1/Ref-1, also called APE1) is a multifunctional enzyme with crucial roles in DNA repair and reduction/oxidation (redox) signaling. APE1 was originally described as an endonuclease in the Base Excision Repair (BER) pathway. Further study revealed it to be a redox signaling hub regulating critical transcription factors (TFs). Although a significant amount of focus has been on the role of APE1 in cancer, recent findings support APE1 as a target in other indications, including ocular diseases [diabetic retinopathy (DR), diabetic macular edema (DME), and age-related macular degeneration (AMD)], inflammatory bowel disease (IBD) and others, where APE1 regulation of crucial TFs impacts important pathways in these diseases. The central responsibilities of APE1 in DNA repair and redox signaling make it an attractive therapeutic target for cancer and other diseases.
Project description:PURPOSE: To assess the ability of patients to predict the need for retreatment with intravitreal ranibizumab in neovascular age-related macular degeneration (NVAMD) based on their perception of visual deterioration or distortion of objects in their everyday environment (environmental Amsler). METHODS: A questionnaire was given to 89 patients undergoing optical coherence tomography (OCT)-guided retreatment with intravitreal ranibizumab for NVAMD following an initial loading regimen of three injections and with at least 12-month follow-up. The patient's opinion on the need for an injection on the current visit, based on their perception of change in environmental Amsler, was recorded. This subjective measure was compared with the objective evaluation of retreatment, based on predefined retreatment criteria comprising of changes in visual acuity and morphological changes on OCT. The patients were then instructed on the technique of environmental Amsler, and this evaluation was repeated. The sensitivity and specificity of patient prediction were analyzed at baseline and after the training. RESULTS: The ability of patients to predict disease activity at baseline showed a sensitivity of 61% and specificity of 96.6%. The area under the receiver operating characteristic curve was 0.8. The presence of macular fluid correlated well with the patient's perception of an abnormal environmental Amsler. After training, the sensitivity and specificity improved to 87.5% and 98.5%, respectively. CONCLUSION: In real life, most patients are able to predict the reactivation of the disease in NVAMD, after 12-month follow-up, after training to monitor their symptoms using the environmental Amsler test.
Project description:Purpose:Anti-vascular endothelial growth factor (VEGF) therapy for neovascular AMD (nvAMD) obtains a variable outcome. We performed a genome-wide association study for anti-VEGF treatment response in nvAMD to identify variants potentially underlying such a variable outcome. Methods:Israeli patients with nvAMD who underwent anti-VEGF treatment (n = 187) were genotyped on a whole exome chip containing approximately 500,000 variants. Genotyping was correlated with delta visual acuity (deltaVA) between baseline and after three injections of anti-VEGF. Top principal components, age, and baseline VA were included in the analysis. Two lead associated variants were genotyped in an independent validation set of patients with nvAMD (n = 108). Results:Linear regression analysis on 5,353,842 variants revealed five exonic variants with an association P value of less than 6 × 10-5. The top variant in the gene VWA3A (P = 1.77 × 10-6) was tested in the validation cohort. The minor allele of the VWA3A variant was associated with worse response to treatment (P = 0.02). The average deltaVA of discovery plus validation was -0.214 logMAR (≈ a gain of 10.7 Early Treatment Diabetic Retinopathy Study letters) for homozygote for the major allele, 0.172 logMAR for heterozygotes (≈ a loss of 8.6 Early Treatment Diabetic Retinopathy Study letters), and 0.21 logMAR for homozygote for the minor allele (≈ a loss of 10.5 Early Treatment Diabetic Retinopathy Study letters). Minor allele carriers had a higher frequency of macular hemorrhage at baseline. Conclusions:An VWA3A gene variant was associated with worse response to anti-VEGF treatment in Israeli patients with nvAMD. The VWA3A protein is a precursor of the multimeric von Willebrand factor which is involved in blood coagulation, a system previously associated with nvAMD.
Project description:Pathological neovascularization, a leading cause of blindness, is seen in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Using a mouse model of hypoxia-driven retinal neovascularization, we find that fibroblast growth factor 21 (FGF21) administration suppresses, and FGF21 deficiency worsens, retinal neovessel growth. The protective effect of FGF21 against neovessel growth was abolished in adiponectin (APN)-deficient mice. FGF21 administration also decreased neovascular lesions in two models of neovascular age-related macular degeneration: very-low-density lipoprotein-receptor-deficient mice with retinal angiomatous proliferation and laser-induced choroidal neovascularization. FGF21 inhibited tumor necrosis ? (TNF-?) expression but did not alter Vegfa expression in neovascular eyes. These data suggest that FGF21 may be a therapeutic target for pathologic vessel growth in patients with neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration.
Project description:This review summarizes the latest findings in the literature of Angiopoietin-2 (Ang-2), Tyrosine-protein kinase receptor (Tie-2) complex, and faricimab along with their involvement for the treatment of retinal vascular diseases in various clinical trials. In ischemic diseases, such as diabetic retinopathy, Ang-2 is upregulated, deactivating Tie-2, resulting in vascular leakage, pericyte loss, and inflammation. Recombinant Angiopeotin-1 (Ang-1), Ang-2-blocking molecules, and inhibitors of vascular endothelial protein tyrosine phosphatase (VE-PTP) decrease inflammation-associated vascular leakage, showing therapeutic effects in diabetes, atherosclerosis, and ocular neovascular diseases. In addition, novel studies show that angiopoietin-like proteins may play an important role in cellular metabolism leading to retinal vascular diseases. Current therapeutic focus combines Ang-Tie targeted drugs with other anti-angiogenic or immune therapies. Clinical studies have identified faricimab, a novel bispecific antibody designed for intravitreal use, to simultaneously bind and neutralize Ang-2 and VEGF-A for treatment of diabetic eye disease. By targeting both Ang-2 and vascular endothelial growth factor-A (VEGF-A), faricimab displays an improved and sustained efficacy over longer treatment intervals, delivering superior vision outcomes for patients with diabetic macular edema and reducing the treatment burden for patients with neovascular age-related macular degeneration and diabetic macular edema. Phase 2 results have produced promising outcomes with regard to efficacy and durability. Faricimab is currently being evaluated in global Phase 3 studies.
Project description:Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy. Bevacizumab, an anti-VEGF monoclonal antibody, is efficacious for these disorders, but requires monthly intravitreal administration, with associated discomfort, cost, and adverse event risk. We hypothesized that a single intravitreal administration of adeno-associated virus (AAV) vector expressing bevacizumab would result in persistent eye expression of bevacizumab and suppress VEGF-induced retinal neovascularization. We constructed an AAV rhesus serotype rh.10 vector to deliver bevacizumab (AAVrh.10BevMab) and assessed its ability to suppress neovascularization in transgenic mice overexpressing human VEGF165 in photoreceptors. Intravitreal AAVrh.10BevMab directed long-term bevacizumab expression in the retinal pigmented epithelium. Treated homozygous mice had reduced levels of neovascularization, with 90±4% reduction 168 days following treatment. Thus, a single administration of AAVrh.10BevMab provides long-term suppression of neovascularization without the costs and risks associated with the multiple administrations required for the current conventional bevacizumab monoclonal drug delivery.