Topical drug delivery to the posterior segment of the eye is a very complex challenge. However, topical delivery is highly desired, to achieve an easy-to-use treatment option for retinal diseases. In this review, we focus on the drug characteristics that are relevant to succeed in this challenge. An overview on the ocular barriers that need to be overcome and some relevant animal models to study ocular pharmacokinetics are given. Furthermore, a summary of substances that were able to reach the posterior segment after eye drop application is provided, as well as an outline of investigated delivery systems to improve ocular drug delivery. Some promising results of substances delivered to the retina suggest that topical treatment of retinal diseases might be possible in the future, which warrants further research.

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Topical Drug Delivery to the Posterior Segment of the Eye

Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) are common retinal vascular diseases responsible for most blindness in the working-age and older population in developed countries. Currently, anti-VEGF agents that block VEGF family ligands, including ranibizumab, bevacizumab (off-label use), brolucizumab, and aflibercept, are the first-line treatment for nAMD and DME. However, due to the complex pathophysiological background of nAMD and DME, non-response, resistance during anti-VEGF therapy, and relapses of the disease are still observed. Moreover, frequent injections are a psychological and economic burden for patients, leading to inadequate adhesion to therapy and a higher risk of complications. Therefore, therapeutic methods are strongly needed to develop and improve, allowing for more satisfactory disease management and lower treatment burden. Currently, the Ang/Tie-2 pathway is a promising therapeutic target for retinal vascular diseases. Faricimab is the first bispecific monoclonal antibody for intravitreal use that can neutralize VEGF and Ang-2. Due to the prolonged activity, faricimab allows extending the interval between successive injections up to three or four months in nAMD and DME patients, which can be a significant benefit for patients and an alternative to implanted drug delivery systems.

/pdf/aflibercept-versus-faricimab-in-the-treatment-of-neovascular-3u5pf5jc.pdf

Aflibercept versus Faricimab in the Treatment of Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema: A Review

The resident macrophages of the central nervous system, microglia, are becoming increasingly implicated as active participants in neuropathology and ageing. Their diverse and changeable morphology is tightly linked with functions they perform, enabling assessment of their activity through image analysis. To better understand the contributions of microglia in health, senescence, and disease, it is necessary to measure morphology with both speed and reliability. A machine learning approach was developed to facilitate automatic classification of images of retinal microglial cells as one of five morphotypes, using a support vector machine (SVM). The area under the receiver operating characteristic curve for this SVM was between 0.99 and 1, indicating strong performance. The densities of the different microglial morphologies were automatically assessed (using the SVM) within wholemount retinal images. Retinas used in the study were sourced from 28 healthy C57/BL6 mice split over three age points (2, 6, and 28-months). The prevalence of 'activated' microglial morphology was significantly higher at 6- and 28-months compared to 2-months (p < .05 and p < .01 respectively), and 'rod' significantly higher at 6-months than 28-months (p < 0.01). The results of the present study propose a robust cell classification SVM, and further evidence of the dynamic role microglia play in ageing. 

https://www.nature.com/articles/s41598-022-05815-6.pdf

Automated characterisation of microglia in ageing mice using image processing and supervised machine learning algorithms

Abstract During long-duration spaceflight, astronauts are exposed to various risks including spaceflight-associated neuro-ocular syndrome, which serves as a risk to astronaut vision and a potential physiological barrier to future spaceflight. When considering exploration missions that may expose astronauts to longer periods of microgravity, radiation exposure, and natural aging processes during spaceflight, more severe changes to functional vision may occur. The macula plays a critical role in central vision and disruptions to this key area in the eye may compromise functional vision and mission performance. In this article, we describe the development of a countermeasure technique to digitally suppress monocular central visual distortion with head-mounted display technology. We report early validation studies with this noninvasive countermeasure in individuals with simulated metamorphopsia. When worn by these individuals, this emerging wearable countermeasure technology has demonstrated a suppression of monocular visual distortion. We describe the considerations and further directions of this head-mounted technology for both astronauts and aging individuals on Earth.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/5D656D429ED4CA8BFF7B915B966B892B/S2631717622000214a.pdf/div-class-title-head-mounted-digital-metamorphopsia-suppression-as-a-countermeasure-for-macular-related-visual-distortions-for-prolonged-spaceflight-missions-and-terrestrial-health-div.pdf

Head-mounted digital metamorphopsia suppression as a countermeasure for macular-related visual distortions for prolonged spaceflight missions and terrestrial health

Purpose Blindness and vision loss are still frequent disabilities associated with a relevant impact on health care and quality of life, and a high economic burden. Supranational programs established by the World Health Organization (WHO), International Agency for the Prevention of Blindness (IAPB), and World Health Assembly (WHA) aim at reducing avoidable visual impairment. Age-related macular degeneration (AMD), diabetic retinopathy (DR), and other retinal diseases are well known causes of visual disability. Since more than a decade, intravitreal agents are available for the treatment of these diseases. The aim of this study is to review whether pharmacotherapy with anti-vascular endothelial growth factor (VEGF) drugs has led to a decrease in the prevalence of blindness with emphasis on AMD and different countries. A brief analysis of other factors correlated to changes in the rate of blindness is also presented. Methods PubMed and Scopus web platforms were used to identify relevant studies on epidemiology of blindness and vision impairment, the influence of intravitreal therapies, and the existence of different vision care models. Additional data and material was searched in web internet accessed by the web browser Firefox. Results Age-standardized prevalence of blindness secondary to AMD has started to decline as testified by a number of studies in different countries. This is due to the adoption of anti-VEGF therapy and its adequate management. The frequency of treatment and regimens applied are indirect signs of successful treatment. Local rules and regulations may represent an obstacle. Conclusions This review shows that by implementing existing health care systems and dispensing adequate therapies in the field of retinal diseases, the prevalence of blindness due to these conditions can decline.

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Anti-VEGF therapies for age-related macular degeneration: a powerful tactical gear or a blunt weapon? The choice is ours.

Age-related macular degeneration (AMD) is one of the most common causes of vision loss. Advanced forms of AMD are seen in primarily two types—neovascular AMD (nAMD) with the presence of choroid neovascularization and non-neovascular AMD (nnAMD) with geographic atrophy. Neovascular AMD is characterized by choroidal neovascularization (CNV), which leads to a cascade of complications, including exudation, leakage, and ultimately fibrosis with photoreceptor loss. Inhibition of VEGF represents the current standard of care. However, there is a tremendous gap between the outcomes in randomized clinical trials and real-world settings. New agents for nAMD might offer the potential to improve treatment outcomes and reduce treatment of frequent intravitreal injections. We summarize all the newer molecules, their pivotal clinical trial results, and their unique mechanisms of action; these include longer-acting agents, combination strategies, sustained release, and genetic therapies.

Prem Nimesh Patel

Papers

New and Innovative Treatments for Neovascular Age-Related Macular Degeneration (nAMD).