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Targeting Angiopoietin in Retinal Vascular Diseases: A Literature Review and Summary of Clinical Trials Involving Faricimab.
Khan, M, Aziz, AA, Shafi, NA, Abbas, T, Khanani, AM
Cells. 2020;(8)
Abstract
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.
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2.
Circulating Leukocyte Alterations and the Development/Progression of Diabetic Retinopathy in Type 1 Diabetic Patients - A Pilot Study.
Obasanmi, G, Lois, N, Armstrong, D, Lavery, NJ, Hombrebueno, JR, Lynch, A, Wright, DM, Chen, M, Xu, H
Current eye research. 2020;(9):1144-1154
Abstract
BACKGROUND/AIMS: The aim of this study was to investigate the relationship between alterations in circulating leukocytes and the initiation and progression of DR in people with type 1 diabetes (T1D). METHODS Forty-one patients with T1D [13 mild non-proliferative DR (mNPDR), 14 active proliferative DR (aPDR) and 14 inactive PDR (iPDR)], and 13 age- and gender-matched healthy controls were recruited prospectively. Circulating leukocytes, including CD4+ and CD8+ T-cells, CD14+CD16-, CD14-CD16+ and CD14+CD16+ monocytes; CD16+HLA-DR- neutrophils, CD19+ B-cells and CD56+ natural killer cells and their cell surface adhesion molecules and chemokine receptors (HLA-DR, CD62L, CCR2, CCR5, CD66a, CD157 and CD305) were examined by flow cytometry. RESULTS In DR patients, compared to healthy controls, increased proportions of neutrophils (p = .0152); reduced proportions of lymphocytes (p = .0002), HLA-DR+ leukocytes (p = .0406) and non-classical monocytes (p = .0204); and reduced expression of CD66a (p = .0048) and CD157 (p = .0007) on CD4+ T cells were observed. Compared to healthy controls, CD19+ B cells were reduced at the mNPDR but not aPDR patients. Total lymphocytes, CD4+ T cells and CD8+ T cells progressively decreased whereas neutrophils, the neutrophil/lymphocyte ratio and the neutrophil/CD4+ ratio progressively increased from early to late stages of DR, reaching statistical significance at the aPDR stage. Longer diabetes duration was associated with a reduced proportion of CD8+ T cells (p = .002) and increased neutrophil/CD8+ ratio (p = .033). CONCLUSIONS In this pilot study, DR is associated with increased innate cellular immunity especially neutrophils and reduced adaptive cellular immunity particularly lymphocytes. Impaired B-cell immunity may play a role in the initiation of DR; whereas impaired T-cell immunity with increased neutrophil response may contribute to progression of DR from non-proliferative to proliferative stages in T1D patients. Large multicenter studies are needed to further understand the immune dysregulation in DR initiation and progression.
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3.
NOD-like Receptors in the Eye: Uncovering Its Role in Diabetic Retinopathy.
Lim, RR, Wieser, ME, Ganga, RR, Barathi, VA, Lakshminarayanan, R, Mohan, RR, Hainsworth, DP, Chaurasia, SS
International journal of molecular sciences. 2020;(3)
Abstract
Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly 50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression. The recent surge in literature associated with NOD-like receptors (NLRs) has gained massive attraction due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, a central phenomenon found in the pathogenesis of ocular diseases including DR. The NLR family of receptors are expressed in different eye tissues during pathological conditions suggesting their potential roles in dry eye, ocular infection, retinal ischemia, cataract, glaucoma, age-related macular degeneration (AMD), diabetic macular edema (DME) and DR. Our group is interested in studying the critical early components involved in the immune cell infiltration and inflammatory pathways involved in the progression of DR. Recently, we reported that NLRP3 inflammasome might play a pivotal role in the pathogenesis of DR. This comprehensive review summarizes the findings of NLRs expression in the ocular tissues with special emphasis on its presence in the retinal microglia and DR pathogenesis.
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4.
Ocular Immunity and Inflammation.
Albini, TA, Davis, JL
Developments in ophthalmology. 2016;:38-45
Abstract
Complex immunologic mechanisms are involved in multiple intraocular diseases. The field of immunology has aided greatly in better understanding and treating inflammation in the posterior segment. While traditional therapy has relied on drugs such as corticosteroids and antimetabolites that exert there effects by multiple mechanisms, the more recently developed biologic immune modulators involve specific mechanisms of action with the potential to significantly reduce side effects relative to more traditional agents. Better understanding of diseases such as age-related macular degeneration or diabetic retinopathy has led to the appreciation of immune mechanisms involved in these diseases and has suggested potential targets for therapy.
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5.
Diabetic Retinopathy: Vascular and Inflammatory Disease.
Semeraro, F, Cancarini, A, dell'Omo, R, Rezzola, S, Romano, MR, Costagliola, C
Journal of diabetes research. 2015;:582060
Abstract
Diabetic retinopathy (DR) is the leading cause of visual impairment in the working-age population of the Western world. The pathogenesis of DR is complex and several vascular, inflammatory, and neuronal mechanisms are involved. Inflammation mediates structural and molecular alterations associated with DR. However, the molecular mechanisms underlying the inflammatory pathways associated with DR are not completely characterized. Previous studies indicate that tissue hypoxia and dysregulation of immune responses associated with diabetes mellitus can induce increased expression of numerous vitreous mediators responsible for DR development. Thus, analysis of vitreous humor obtained from diabetic patients has made it possible to identify some of the mediators (cytokines, chemokines, and other factors) responsible for DR pathogenesis. Further studies are needed to better understand the relationship between inflammation and DR. Herein the main vitreous-related factors triggering the occurrence of retinal complication in diabetes are highlighted.
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6.
Complement involvement in neovascular ocular diseases.
Yanai, R, Thanos, A, Connor, KM
Advances in experimental medicine and biology. 2012;:161-83
Abstract
Pathological neovascularization (NV) is a hallmark of late stage neovascular age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinopathy of prematurity (ROP). There is accumulating evidence that alterations in inflammatory and immune system pathways that arise from genetic differences, injury, and disease can predispose individuals to retinal neovascular eye diseases. Yet the mechanism of disease progression with respect to the complement system in these maladies is not fully understood. Recent studies have implicated the complement system as an emerging player in the etiology of several retinal diseases. We will summarize herein several of the complement system pathways known to be involved in ocular neovascular pathologies. Current treatment for many neovascular eye diseases focuses on suppression of NV with laser ablation, photodynamic therapy, or anti-VEGF angiogenic inhibitors. However, these treatments do not address the underlying cause of many of these diseases. A clear understanding of the cellular and molecular mechanisms could bring a major shift in our approach to disease treatment and prevention.