The complement system: a novel therapeutic target for age-related macular degeneration.

INTRODUCTION: With the recent FDA approvals of pegcetacoplan (SYFOVRE, Apellis Pharmaceuticals) and avacincaptad pegol (IZERVAY, Astellas Pharmaceuticals), modulation of the complement system has emerged as a promising therapeutic approach for slowing progression of geographic atrophy (GA) in AMD. AREAS COVERED: This article reviews the current understanding of the complement system, its role in AMD, and the various complement-targeting therapies in development for the treatment of GA, including monoclonal antibodies, aptamers, protein analogs, and gene therapies. Approved and investigational agents have largely focused on interfering with the activity of complement components 3 and 5, owing to their central roles in the classical, lectin, and alternative complement pathways. Other investigational therapies have targeted formation of membrane attack complex (a terminal step in the complement cascade which leads to cell lysis), complement factors H and I (which serve regulatory functions in the alternative pathway), complement factors B and D (within the alternative pathway), and complement component 1 (within the classical pathway). Clinical trials investigating these agents are summarized, and the potential benefits and limitations of these therapies are discussed. EXPERT OPINION: Targeting the complement system is a promising therapeutic approach for slowing the progression of GA in AMD, potentially improving visual outcomes. However, increased risk of exudative conversion must be considered, and further research is required to identify clinical criteria and best practices for initiating complement inhibitor therapy for GA.

Rhegmatogenous Retinal Detachment in Syphilitic Uveitis: A Case Series and Comprehensive Review of the Literature.

PURPOSE: Uveitis is the most common ocular manifestation of syphilis. However, an association between syphilitic uveitis and rhegmatogenous retinal detachment (RRD) is not widely recognized. We report a consecutive series of six new cases of syphilitic uveitis complicated by RRD and describe the typical characteristics, clinical course, and surgical management of such cases. METHODS: Consecutive case series and comprehensive review of the literature. RESULTS: We identified a total of 19 cases (23 eyes) with syphilitic uveitis subsequently complicated by RRD, including six new cases (seven eyes) reported here and 13 cases (16 eyes) previously reported in the literature. Fifteen patients (79%) were positive for human immunodeficiency virus (HIV) and not on combination antiretroviral therapy. Most retinal detachments developed within two months of uveitis presentation; retinal breaks were often found in areas of previous retinitis. Sixteen eyes (70%) were complicated by early proliferative vitreoretinopathy. Twenty-one eyes underwent surgical repair, of which six (26%) suffered re-detachment. Surgical management commonly involved pars-plana vitrectomy and silicone oil tamponade, with or without scleral buckling. Visual outcomes were generally poor: only six eyes (26%) attained visual acuity of 20/40 or better and 11 eyes (48%) remained 20/200 or worse. CONCLUSIONS: Patients with syphilitic uveitis, as with viral retinitis, should be monitored closely for the development of retinal tears and RRD. A combination of pars plana vitrectomy with silicone oil tamponade and/or scleral buckle placement is a prudent surgical approach to most cases of syphilitic RRD, although visual prognosis remains guarded.

The evolving therapeutic landscape of diabetic retinopathy.

INTRODUCTION: Diabetic retinopathy (DR) is a leading cause of blindness worldwide. Recent decades have seen rapid progress in the management of diabetic eye disease, evolving from pituitary ablation to photocoagulation and intravitreal pharmacotherapy. The advent of effective intravitreal drugs inhibiting vascular endothelial growth factor (VEGF) marked a new era in DR therapy. Sustained innovation has since produced several promising biologics targeting angiogenesis, inflammation, oxidative stress, and neurodegeneration. AREAS COVERED: This review surveys traditional, contemporary, and emerging therapeutics for DR, with an emphasis on anti-VEGF therapies, receptor tyrosine kinase inhibitors, angiopoietin-Tie2 pathway inhibitors, integrin pathway inhibitors, gene therapy 'biofactory' approaches, and novel systemic therapies. Some of these investigational therapies are being delivered intravitreally via sustained release technologies for extended durability. Other investigational agents are being delivered non-invasively via topical and systemic routes. These strategies hold promise for early and long-lasting treatment of DR. EXPERT OPINION: The evolving therapeutic landscape of DR is rapidly expanding our toolkit for the effective and durable treatment of blinding eye disease. However, further research is required to validate the efficacy of novel therapeutics and characterize real world outcomes.

Molecular Genetic Mechanisms in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is among the leading causes of irreversible blindness worldwide. In addition to environmental risk factors, such as tobacco use and diet, genetic background has long been established as a major risk factor for the development of AMD. However, our ability to predict disease risk and personalize treatment remains limited by our nascent understanding of the molecular mechanisms underlying AMD pathogenesis. Research into the molecular genetics of AMD over the past two decades has uncovered 52 independent gene variants and 34 independent loci that are implicated in the development of AMD, accounting for over half of the genetic risk. This research has helped delineate at least five major pathways that may be disrupted in the pathogenesis of AMD: the complement system, extracellular matrix remodeling, lipid metabolism, angiogenesis, and oxidative stress response. This review surveys our current understanding of each of these disease mechanisms, in turn, along with their associated pathogenic gene variants. Continued research into the molecular genetics of AMD holds great promise for the development of precision-targeted, personalized therapies that bring us closer to a cure for this debilitating disease.

Genetics of Diabetic Retinopathy, a Leading Cause of Irreversible Blindness in the Industrialized World.

Diabetic retinopathy (DR) is a chronic complication of diabetes and a leading cause of blindness in the industrialized world. Traditional risk factors, such as glycemic control and duration of diabetes, are unable to explain why some individuals remain protected while others progress to a more severe form of the disease. Differences are also observed in DR heritability as well as the response to anti-vascular endothelial growth factor (VEGF) treatment. This review discusses various aspects of genetics in DR to shed light on DR pathogenesis and treatment. First, we discuss the global burden of DR followed by a discussion on disease pathogenesis as well as the role genetics plays in the prevalence and progression of DR. Subsequently, we provide a review of studies related to DR's genetic contribution, such as candidate gene studies, linkage studies, and genome-wide association studies (GWAS) as well as other clinical and meta-analysis studies that have identified putative candidate genes. With the advent of newer cutting-edge technologies, identifying the genetic components in DR has played an important role in understanding DR incidence, progression, and response to treatment, thereby developing newer therapeutic targets and therapies.

Retinal oximetry in glaucoma: investigations and findings reviewed.

Abnormalities of the retinal blood supply have been widely implicated in primary open-angle glaucoma (POAG). Impaired blood supply to the retina and optic nerve head (ONH) may be a primary pathophysiologic mechanism contributing to POAG ('vascular hypothesis'). However, the decreased metabolic activity of atrophic tissue is itself known to induce both vascular changes and decreased blood flow due to reduced oxygen demand. Therefore, primary nonvascular factors could potentially induce glaucomatous atrophy, with subsequent secondary vascular pathology ('mechanical hypothesis'). Retinal oximetry holds great promise in the investigation of glaucoma pathogenesis, as it can provide useful data on retinal metabolic oxygen demand, especially when combined with measurements of retinal blood flow. This review surveys the research on retinal metabolism in POAG using spectroscopic retinal oximetry. The use of mathematical models in combination with oximetric data to investigate the role of retinal metabolism and oxygen supply in POAG is also discussed.