Progress of clinical therapies for dry age-related macular degeneration

Dry age-related macular degeneration (AMD) is a progressive blinding disease that currently affects millions of people worldwide with no successful treatment available. Significant research efforts are currently underway to develop therapies aimed at slowing the progression of this disease or, more notably, reversing it. Here the therapies which have reached clinical trial for treatment of dry AMD were reviewed. A thorough search of PubMed, Embase, and Clinicaltrials.gov has led to a comprehensive collection of the most recent strategies being evaluated. This review also endeavors to assess the status and future directions of therapeutics for this debilitating condition.

Complement cascade inhibition in geographic atrophy: a review

The 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.

Differential Circulating MicroRNA Expression in Age-Related Macular Degeneration

This study explored the expression of several miRNAs reported to be deregulated in age-related macular degeneration (AMD). Total RNA was isolated from sera from patients with dry AMD (n = 12), wet AMD (n = 14), and controls (n = 10). Forty-two previously investigated miRNAs were selected based on published data and their role in AMD pathogenesis, such as angiogenic and inflammatory effects, and were co-analysed using a miRCURY LNA miRNA SYBR® Green PCR kit via quantitative real-time polymerase chain reaction (qRT-PCR) to validate their presence. Unsupervised hierarchical clustering indicated that AMD serum specimens have a different miRNA profile to healthy controls. We successfully validated the differentially regulated miRNAs in serum from AMD patients versus controls. Eight miRNAs (hsa-let-7a-5p, hsa-let-7d-5p, hsa-miR-23a-3p, hsa-miR-301a-3p, hsa-miR-361-5p, hsa-miR-27b-3p, hsa-miR-874-3p, hsa-miR-19b-1-5p) showed higher expression in the serum of dry AMD patients than wet AMD patients and compared with healthy controls. Increased quantities of certain miRNAs in the serum of AMD patients indicate that these miRNAs could potentially serve as diagnostic AMD biomarkers and might be used as future AMD treatment targets. The discovery of significant serum miRNA biomarkers in AMD patients would provide an easy screening tool for at-risk populations.

Assessment of Neutrophil-Lymphocyte Ratios in Patients with Dry Age-related Macular Degeneration

Purpose: To assess the significance of neutrophil-lymphocyte ratio (NLR) as an inflammatory indicator in patients with dry age-related macular degeneration (AMD). Study design: A retrospective case-control study.Methods: Clinical diagnosis along with complete blood count (CBC) results were extracted from hospital and laboratory information systems for patients with dry-AMD and age/gender-matched controls attending the ophthalmology clinic at King Abdulaziz medical city, Jeddah, Saudi Arabia, between 2018-2020. NLR was calculated by dividing the neutrophil by the lymphocyte count. Results: This study captured 90 patients diagnosed with dry-AMD and 270 control subjects without AMD. The mean of ages 70 and 71 years old for cases and controls, respectively. In univariate analysis, there were no significant differences in CBC results between cases and control. In NLR, dry-AMD patients have a slightly higher mean than the control group; however, this increase was not statistically significant (P-value 0.8). In the NLR model, age and gender were statistically significant factors affecting the NLR values in dry-AMD (P-value 0.03, 0.01 respectively). Conclusion: as a systemic inflammatory biomarker, NLR alone could not predict dry-AMD. However, the slight increase in the NLR values may be helpful if augmented with other laboratory measurements to aid in early disease prediction.

Cell Stiffening Contributes to Complement-mediated Injury of Choroidal Endothelial Cells in Early AMD

Age-related macular degeneration (AMD) is the leading cause of blindness in the aging population. Yet, no therapies exist for ~85% of all AMD patients who have the dry form that is marked by degeneration of the retinal pigment epithelium (RPE) and underlying choroidal vasculature. As the choroidal vessels are crucial for RPE development and maintenance, understanding how they degenerate may lead to effective therapies for dry AMD. One likely causative factor for choroidal vascular loss is the cytolytic membrane attack complex (MAC) of the complement pathway that is abundant on choroidal vessels of humans with early dry AMD. To examine this possibility, we studied the effect of complement activation on choroidal endothelial cells (ECs) isolated from a rhesus monkey model of early AMD that, we report, exhibits MAC deposition and choriocapillaris endothelial loss similar to that seen in human early AMD. Treatment of choroidal ECs from AMD eyes with complement-competent normal human serum caused extensive actin cytoskeletal injury that was significantly less pronounced in choroidal ECs from young normal monkey eyes. We further show that ECs from AMD eyes are significantly stiffer than their younger counterparts and exhibit peripheral actin organization that is distinct from the longitudinal stress fibers in young ECs. Finally, these differences in complement susceptibility and mechanostructural properties were found to be regulated by the differential activity of small GTPases Rac and Rho because Rac inhibition in AMD cells led to simultaneous reduction in stiffness and complement susceptibility while Rho inhibition in young cells exacerbated complement injury. Thus, by identifying cell stiffness and cytoskeletal regulators Rac and Rho as important determinants of complement susceptibility, the current findings offer a new mechanistic insight into choroidal vascular loss in early AMD that warrants further investigation for assessment of translational potential.

Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration

The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA–induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD.

Vascular Density Changes after Nanosecond Laser Therapy in Dry AMD

Introduction: АМD is a disease of social significance and an increasing incidence. By 2040, patients are expected to reach 300 million. 90% of them have non-exudative form while only10% have exudative AMD. The nanosecond laser (2RT, Ellex) is the first patented therapy for dry AMD. It presents a new hope in the prophylaxis of the more aggressive exudative form. Aim: The aim of this study is to present an innovative treatment for dry AMD; to describe the mechanism of action of 2RT; to show first clinical results and to prove the functional efficiency of the therapy by pre and post treatment analysis of vascular density. Methods: Nanosecond laser (2RT, Ellex) was used. Patients were followed with visual acuity, contrast sensitivity (F.A.C.T.101), Fluorescein angiography (FA)Fundus auto-fluorescens (FAF), OCT, Angio-OCT. Statistical analysis of vascular density (foveal and peri-foveal superficial and deep) was done. Results: A significant improvement in vascular density in the macula was observed 3-6 months after the treatment in all patients with dry AMD. In 40% of cases a reduction of the drusen was observed. No increase of the atrophic changes was observed. Conclusions: The main goal of the treatment is to ameliorate the degenerative process by tissue stimulation and rejuvenation. Vascular density increase after 2RT treatment does prove the functional improvement and efficacy of the therapy.

Complement Inhibitors in Age-Related Macular Degeneration: A Potential Therapeutic Option

Age-related macular degeneration (AMD) is a multifactorial disease, which can culminate in irreversible vision loss and blindness in elderly. Nowadays, there is a big gap between dry AMD and wet AMD on treatment. Accounting for nearly 90% of AMD, dry AMD still lacks effective treatment. Numerous genetic and molecular researches have confirmed the significant role of the complement system in the pathogenesis of AMD, leading to a deeper exploration of complement inhibitors in the treatment of AMD. To date, at least 14 different complement inhibitors have been or are being explored in AMD in almost 40 clinical trials. While most complement inhibitors fail to treat AMD successfully, two of them are effective in inhibiting the rate of GA progression in phase II clinical trials, and both of them successfully entered phase III trials. Furthermore, recently emerging complement gene therapy and combination therapy also offer new opportunities to treat AMD in the future. In this review, we aim to introduce genetic and molecular associations between the complement system and AMD, provide the updated progress in complement inhibitors in AMD on clinical trials, and discuss the challenges and prospects of complement therapeutic strategies in AMD.

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

Outer 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.