scholarly journals Complement cascade inhibition in geographic atrophy: a review

Eye ◽  
2022 ◽  
Author(s):  
Dhaval Desai ◽  
Pravin U. Dugel
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Serum Proteins ◽  
Geographic Atrophy ◽  
Innate Immune ◽  
Age Related Macular Degeneration ◽  
Complement Cascade ◽  
Complement Factors ◽  
Age Related ◽  
Dry Amd

AbstractThe pathophysiology of dry age-related macular degeneration (AMD) and specifically geographic atrophy (GA) has been linked to the complement cascade. This cascade is part of the innate immune system and is made up of the classical, alternative, and lectin pathways. The pathways comprise a system of plasma and membrane-associated serum proteins that are activated with identification of a nonself entity. A number of these proteins have been implicated in the development and progression of dry AMD. The three pathways converge at C3 and cascade down through C5, making both of these proteins viable targets for the treatment of dry AMD. In addition, there are a number of complement factors, CFB, CFD, CFH, and CFI, which are potential therapeutic targets as well. Several different complement-directed therapeutics are being studied for the treatment of dry AMD with the hope that one of these approaches will emerge as the first approved treatment for GA.

scholarly journals Therapeutic Approaches with Intravitreal Injections in Geographic Atrophy Secondary to Age-Related Macular Degeneration: Current Drugs and Potential Molecules

2019 ◽  
Author(s):  
Marcella Nebbioso ◽  
Alessandro Lambiase ◽  
Alberto Cerini ◽  
Paolo Giuseppe Limoli ◽  
Maurizio La Cava ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Macular Degeneration ◽  
Ganglion Cells ◽  
Therapeutic Agents ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
New Drugs ◽  
Complement Cascade ◽  
Age Related ◽  
Dry Amd

The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. The changes in the correct visual acuity and the reduction in geographic atrophy progression were evaluated. Several new drugs have shown some promising results, including those targeting the complement cascade and agents called neuroprotective. The action potential of the two groups of drugs is to block the complement cascade model for immunomodulating agents, and prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. To the best of knowledge, and after extensive studies on the matter, there are still many investigations to be carried out on dry AMD in collaboration between researchers. They will have to identify truly effective molecules, understand the practical potential of pluripotent stem cells, and refine gene therapies. Only in-depth clinical trials will be able to allow the most appropriate and personalized treatments for each dry AMD patient.

scholarly journals Therapeutic Approaches with Intravitreal Injections in Geographic Atrophy Secondary to Age-Related Macular Degeneration: Current Drugs and Potential Molecules

2019 ◽  
Vol 20 (7) ◽  
pp. 1693 ◽  
Author(s):  
Marcella Nebbioso ◽  
Alessandro Lambiase ◽  
Alberto Cerini ◽  
Paolo Giuseppe Limoli ◽  
Maurizio La Cava ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Ganglion Cells ◽  
Therapeutic Agents ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
New Drugs ◽  
Complement Cascade ◽  
Complement Inhibitors ◽  
Age Related ◽  
Dry Amd

The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory agents. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. Changes in the correct visual acuity and reduction in geographic atrophy progression were evaluated. Several new drugs have shown promising results, including those targeting the complement cascade and neuroprotective agents. The potential action of the two groups of drugs is to block complement cascade upregulation of immunomodulating agents, and to prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. Our analysis indicates that finding treatments for dry AMD will require continued collaboration among researchers to identify additional molecular targets and to fully interrogate the utility of pluripotent stem cells for personalized therapy.

scholarly journals Outer retinal tubulation formation and clinical course of advanced age-related macular degeneration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alessandro Arrigo ◽  
Emanuela Aragona ◽  
Ottavia Battaglia ◽  
Andrea Saladino ◽  
Alessia Amato ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Müller Cells ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Advanced Age ◽  
Age Related ◽  
Dry Amd ◽  
Foveal Sparing ◽  
Wet Amd

AbstractOuter retinal tubulations (ORT) are a relatively new finding characterizing outer retinal atrophy. The main aim of the present study was to describe ORT development in advanced age-related macular degeneration (AMD) and to assess its relationship with disease’s severity. Patients with advanced AMD characterized either by macular neovascularization or geographic atrophy, showing signs of outer retinal disruption or retinal pigment epithelium atrophy on structural optical coherence tomography (OCT) at the inclusion examination were prospectively recruited. All the patients underwent complete ophthalmologic evaluation, structural OCT scans and fundus autofluorescence imaging. The planned follow-up was of 3-years. Main outcome measures were ORT prevalence, mechanism of ORT formation, mean time needed for complete ORT formation, best-corrected visual acuity (BCVA), definitely decreased autofluorescence (DDAF) area, questionably decreased autofluorescence (QDAF) area, retinal layer thickness, foveal sparing, number of intravitreal injections. We also assessed the possible role of external limiting membrane (ELM) and Müller cells in ORT pathogenesis. Seventy eyes (70 patients) were included; 43 showed dry AMD evolving to geographic atrophy, while 27 displayed the features of wet AMD. Baseline BCVA was 0.5 ± 0.5 LogMAR, decreasing to 0.9 ± 0.5 LogMAR at the 3-year follow-up (p < 0.01). We detected completely formed ORT in 26/70 eyes (37%), subdivided as follows: 20 eyes (77%) wet AMD and 6 eyes (23%) dry AMD (p < 0.01). ORT took 18 ± 8 months (range 3–35 months) to develop fully. We described the steps leading to ORT development, characterized by progressive involvement of, and damage to the photoreceptors, the ELM and the RPE. Eyes displaying ORT were associated with a smaller QDAF area, less retinal layers damage and lower rate of foveal sparing than eyes free of ORT (p < 0.01). We also described pigment accumulations simulating ORT, which were detected in 16/70 eyes (23%), associated with a greater loss of foveal sparing, increased DDAF area and smaller QDAF area at the 3-year follow-up (p < 0.01). In conclusion, this study provided a description of the steps leading to ORT development in AMD. ELM and Müller cells showed a role in ORT pathogenesis. Furthermore, we described a subtype of pigment hypertrophy mimicking ORT, evaluating its clinical utility.

Non-Nutritional Medical Treatments in Dry-Form (Non-Neovascular) Age-Related Macular Degeneration

2017 ◽  
pp. 145-148
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
The Elderly ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Medical Treatments ◽  
Age Related ◽  
Dry Amd ◽  
Disease Study ◽  
Developed World

Age-related macular degeneration (AMD) is the major cause of blindness for the elderly population in the developed world. Although vision loss is mainly due to the neovascular form, dry AMD remains a challenge for ophthalmologists because of the lack of effective therapies. The Age-Related Eye Disease Study (AREDS) demonstrated the protective effect of dietary supplementation of antioxidants to slow down the progression of dry AMD. On the other hand, there has been no proven drug treatment for dry AMD to date. This review is aimed to discuss recent non-nutritional treatments for dry AMD and geographic atrophy.

scholarly journals DC-SIGN activation mediates the differential effects of SAP and CRP on the innate immune system and inhibits fibrosis in mice

2015 ◽  
Vol 112 (27) ◽  
pp. 8385-8390 ◽  
Author(s):  
Nehemiah Cox ◽  
Darrell Pilling ◽  
Richard H. Gomer
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Serum Proteins ◽  
Phase 1 ◽  
The United States ◽  
Innate Immune ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Acute Lung Inflammation ◽  
Neutrophil Accumulation

Fibrosis is caused by scar tissue formation in internal organs and is associated with 45% of deaths in the United States. Two closely related human serum proteins, serum amyloid P (SAP) and C-reactive protein (CRP), strongly affect fibrosis. In multiple animal models, and in Phase 1 and Phase 2 clinical trials, SAP affects several aspects of the innate immune system to reduce fibrosis, whereas CRP appears to potentiate fibrosis. However, SAP and CRP bind the same Fcγ receptors (FcγR) with similar affinities, and why SAP and CRP have opposing effects is unknown. Here, we report that SAP but not CRP binds the receptor DC-SIGN (SIGN-R1) to affect the innate immune system, and that FcγR are not necessary for SAP function. A polycyclic aminothiazole DC-SIGN ligand and anti–DC-SIGN antibodies mimic SAP effects in vitro. In mice, the aminothiazole reduces neutrophil accumulation in a model of acute lung inflammation and, at 0.001 mg/kg, alleviates pulmonary fibrosis by increasing levels of the immunosuppressant IL-10. DC-SIGN (SIGN-R1) is present on mouse lung epithelial cells, and SAP and the aminothiazole potentiate IL-10 production from these cells. Our data suggest that SAP activates DC-SIGN to regulate the innate immune system differently from CRP, and that DC-SIGN is a target for antifibrotics.

scholarly journals Systems Biology Profiling of AMD on the Basis of Gene Expression

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Mones S. Abu-Asab ◽  
Jose Salazar ◽  
Jingsheng Tuo ◽  
Chi-Chao Chan
Keyword(s):  
Gene Expression ◽  
Systems Biology ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Disease Spectrum ◽  
Age Related ◽  
Dry Amd ◽  
Pathway Networks

Genetic pathways underlying the initiation and progression of age-related macular degeneration (AMD) have not been yet sufficiently revealed, and the correlations of AMD’s genotypes, phenotypes, and disease spectrum are still awaiting resolution. We are tackling both problems with systems biology phylogenetic parsimony analysis. Gene expression data (GSE29801: NCBI, Geo) of macular and extramacular specimens of the retinas and retinal pigment epithelium (RPE) choroid complexes representing dry AMD without geographic atrophy (GA), choroidal neovascularization (CNV), GA, as well as pre-AMD and subclinical pre-AMD were polarized against their respective normal specimens and then processed through the parsimony program MIX to produce phylogenetic cladograms. Gene lists from cladograms’ nodes were processed in Genomatix GePS to reveal the affected signaling pathway networks. Cladograms exposed a highly heterogeneous transcriptomic profiles within all the conventional phenotypes. Moreover, clades and nodal synapomorphies did not support the classical AMD phenotypes as valid transcriptomal genotypes. Gene lists defined by cladogram nodes showed that the AMD-related deregulations occurring in the neural retina were different from those in RPE-choroidal tissue. Our analysis suggests a more complex transcriptional profile of the phenotypes than expected. Evaluation of the disease in much earlier stages is needed to elucidate the initial events of AMD.

Age-related macular degeneration treatment: current view (literature review)

2014 ◽  
Vol 21 (1) ◽  
pp. 43-50
Author(s):  
Monika Kalesinskaitė ◽  
Diana Uljanionok ◽  
Rasa Liutkevičienė
Keyword(s):  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Treatment Options ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Current View ◽  
Neovascular Amd ◽  
Age Related ◽  
Dry Amd

Age-related macular degeneration (AMD) – is a damage of the macula, accompanied by a significant and irreversible loss of central vision. It is a major cause of blindness and visual impairment in older adults (>60 years). Damage of the retina always includes both eyes, though the intensity can vary. Early AMD is defined as the presence of drusen and retinal pigmentary abnormalities (RPE); late AMD includes dry AMD (geographic atrophy of the RPE in the absence of neovascular AMD) or neovascular AMD  (detachment of the retinal pigment epithelium, hemorrhages, and/or scars). Unfortunately, the etiology and pathogenesis of AMD aren’t fully understood up to now, so treatment options are limited and not always effective. This article briefly reviews the options of initial and late forms of AMD treatment

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