Targeting the Eye: RNA-Based Therapies, Interferences, and Delivery Strategies

RNA-Based Therapeutics: Ready for Delivery?

Welcome to this special issue of PPAR research dedicated to “PPARs in Eye Biology and Disease.” PPARs are well known to regulate the expression of genes involved in lipid and glucose metabolism. Very recently, these transcription factors have been demonstrated to modulate proliferative, inflammatory, and oxidative stress responses, including those that happen in the eye. We have collected a comprehensive group of review papers that are focused on discussing the relationships of PPARs with choroidal neovascularization, inflammation, and redox balance, as well as perspective therapeutic potentials of PPAR modulators in eye diseases. Angiogenesis is an important element of normal development and neovascularization which occurs normally in wound healing. However, neoangiogenesis is unfortunately also associated with various pathological ocular conditions including corneal neovascularization secondary to graft rejection and traumatic, chemical, and infectious insults; diabetic complications in both the anterior and posterior segments; retinoproliferative disease secondary to vaso-occlusive events; as well as choroidal neovascularization associated with trauma, high myopia, genetic disease, and age-related macular degeneration (AMD). Of these, AMD is currently the leading cause of blindness in the developed world. As such, much effort and expense is and has been invested in understanding and seeking cures for this devastating condition. Although there is little direct evidence linking PPAR action to AMD, there is a growing body of literature demonstrating that PPARs may be involved in various chemical pathways associated with AMD. In this issue, three papers authored by respected experts in the field are presented which review what we now know about the relationship between the 3 PPAR isoforms, α, β, and δ, and ocular angiogenesis with emphasis on AMD. Bishop-Bailey has reviewed PPARβ/δ-mediated angiogenesis in the context of ocular disorders. Gehlbach et al. have briefly discussed the PPAR-α ligands as potential therapeutic agents for wet AMD. Chan et al. have comprehensively described PPARs with the development of AMD. There now appears to be ample data in the peer-reviewed literature to encourage further study of the link between PPARs and AMD, and investigate the therapeutic potential of PPARs. In addition, an authoritative fourth paper authored by Pershadsingh is also offered to address PPARγ agonists as potential therapeutics for non-AMD proliferative retinopathies. Inflammatory signaling participates in the development of different forms of eye diseases. Inflammatory injury happens under the conditions in which pathoangiogenic signaling is activated in acute inflammatory responses; chronic inflammation is triggered by oxidative stress in diabetic retinopathy and atrophic AMD. The majority of reports documented in the literature support an anti-inflammatory role of PPARs, in particular PPARγ, by blocking the release of inflammatory mediators from activated immune cells in vitro and dampening inflammation in animal models. Minghetti et al. have explored the roles of PPARγ in microglial cell functions and therapeutic potentials of PPARγ ligands on ocular diseases such as AMD, diabetic retinopathy, autoimmune uveitis, and optic neuritis. Yanagi has evaluated the role of PPARγ in the breakdown of blood-retinal barrier, providing strong evidence that targeting PPARγ would be beneficial to diabetic retinopathy via maintaining the integrity of blood-retinal barrier. Phipps et al. have extensively reviewed the literature regarding the role of lymphocytes in thyroid eye disease-related inflammation, offering PPARγ ligands as a therapeutic approach via inhibition of inflammatory signaling in activated lymphocytes and fibroblasts. The potential regulation of redox balance by PPARs in the eye has been recently suggested and may constitute a new, exciting research field over the next few years. Phagocytosis of tips of rod outer segments' selectively upregulates expression of PPARγ in retinal pigment epithelial (RPE) cells, suggesting that PPARγ activation might deal with oxidative stress during RPE cell phagocytosis. Oxidative stress is a major risk factor causing RPE cell degeneration since RPE cells are exposed to high levels of free radicals due to phagocytosis of oxidized photoreceptor outer segments, intense light irradiation, and high oxygen consumption in the macular area. PPARγ ligands protect a variety of cell types from oxidative stress injury in vitro, including retinal cells, though no in vivo data are available yet. Chang et al. have briefly reviewed the cytoprotective effects of an endogenous PPARγ agonist, 15d-PGJ2, on oxidative stress-induced RPE cell death. PPARs are emerging as potential targets for drugs that might be used in the treatment of ocular diseases in which PPAR activities play a key role in disease pathology. It is our hope that this special issue will serve as a seed stimulating broad interests to pursue therapeutic avenues of PPARs in eye diseases. The outcomes of such investigations will undoubtedly shed light on the roles of PPARs in eye diseases and possibly identify new roles of PPARs in the etiology of eye diseases. Suofu Qin Roy S. Chuck

To investigate the redox state of human serum albumin concerning cysteine-34 as a possible systemic redox marker in patients with different eye diseases with and without complications and with consideration of possible effects of age. Cataract (CAT), glaucoma, age-related macular degeneration (AMD), diabetes mellitus (DM), diabetic retinopathy and hypertension were the pathologies investigated. Albumin redox state concerning cysteine-34 was measured by high-performance liquid chromatography with fluorescence detection. The separation gives three fractions: the fully reduced form containing a thiol group, the disulphide form and a higher oxidized form. Statistical analysis was done by Student's t-test, analysis of variance and stepwise regression analysis. Albumin as a systemic marker for oxidative stress was shifted to a more oxidized state by DM. An even stronger shift to the oxidized form was observed in patients with proliferative diabetic retinopathy. Notably, these effects were independent from age. In contrast, CAT and AMD had no influence on serum albumin redox state. Serum albumin is not shifted to more oxidized forms by localized oxidative stress, but it is in systemic diseases like DM.

Introduction In the retina, noncoding RNA (ncRNA) plays an integral role in regulating apoptosis, inflammatory responses, visual perception, and photo-transduction, with altered levels reported in diseased states. Areas covered MicroRNA (miRNA), a class of ncRNA, regulates post-transcription gene expression through the binding of complementary sites of target messenger RNA (mRNA) with resulting translational repression. Small-interfering RNA (siRNA) is a double-stranded RNA (dsRNA) that regulates gene expression, leading to selective silencing of genes through a process called RNA interference (RNAi). Another form of RNAi involves short hairpin RNA (shRNA). In age-related macular degeneration (AMD) and diabetic retinopathy (DR), miRNA has been implicated in the regulation of angiogenesis, oxidative stress, immune response, and inflammation. Expert opinion Many RNA-based therapies in development are conveniently administered intravitreally, with the potential for pan-retinal effect. The majority of these RNA therapeutics are synthetic ncRNA’s and hold promise for the treatment of AMD, DR, and inherited retinal diseases (IRDs). These RNA-based therapies include siRNA therapy with its high specificity, shRNA to ‘knock down’ autosomal dominant toxic gain of function-mutated genes, antisense oligonucleotides (ASOs), which can restore splicing defects, and translational read-through inducing drugs (TRIDs) to increase expression of full-length protein from genes with premature stop codons.

The occurrence and development of biological tissue diseases are closely related to their biomechanical properties. In recent years, significant achievements have been made in the research on the biomechanical properties of the cornea and sclera, and the research on the association between the biomechanics of the posterior eye and eye diseases has also been continuously advanced. This review systematically collates the research on the biomechanical characteristics of the retina, Bruch's membrane-choroid complex (BMCC), and optic nerve head. The retina is anisotropic, with the elastic modulus increasing from the inner layer to the photosensitive layer. The internal limiting membrane has high mechanical strength and stiffness, and these properties change with age. The stiffness of the BMCC increases with strain, and its biomechanical changes are closely linked to aging and age-related diseases. The stress-strain pattern of the optic nerve head is affected by multiple factors and plays a crucial role in diseases such as glaucoma. These biomechanical properties are of great significance in the pathogenesis of diseases such as age-related macular degeneration, diabetic retinopathy, and glaucomatous optic neuropathy, and are also widely applied in the optimization of clinical surgeries, disease monitoring, and diagnosis. However, currently, the research on the biomechanics of the posterior segment of the eye is still in its infancy. The mechanical regulation mechanisms of multiple factors such as age, intraocular pressure, blood flow, and axial length have not been fully elucidated, and aspects such as matrix protein remodeling and post-translational modifications also require in-depth research.

RNA therapeutics in ophthalmology - translation to clinical trials

To estimate the prevalence of cataract, glaucoma, age-related maculopathy (ARM) and diabetic retinopathy (DR) in the adult Finnish population. A representative cross-sectional sample of the Finnish population aged 30 years and older. Of the 7979 eligible people, 7413 (93%) were interviewed and/or examined. The interview included self-reported doctor-made diagnoses of cataract, glaucoma, degenerative fundus changes (mainly ARM) or DR. Information on self-reported eye diseases was complemented with data from national registers, and case records were gathered for non-participants and persons with visual acuity (VA) < 0.5 or reporting difficulties in vision or eye diseases without assessed VA. Based on self-reported and/or register-based data the estimated total prevalences of cataract, glaucoma, ARM and DR in the study population were 10%, 5%, 4% and 1%, respectively. All these chronic eye diseases increased with age (p < 0.001). The corresponding prevalences for persons aged 65 and older were 34%, 13%, 12% and 2%, respectively. Cataract and glaucoma were more common in women than in men [odds ratio (OR) 1.55, 95% confidence interval (CI) 1.26-1.91; OR 1.57, 95% CI 1.24-1.98, respectively]. The most prevalent eye diseases in people with visual impairment (VA < or = 0.25) were ARM (37%), unoperated cataract (27%), glaucoma (22%) and DR (7%). The high prevalence of these mainly age-related eye diseases, together with increasing life expectancy, mean that continuous efforts are needed to identify and treat eye diseases in order to maintain patients' quality of life and to alleviate the social and economic burden of serious eye diseases.

AI telemedicine screening in ophthalmology: health economic considerations

Cohort Studies: Design and Pitfalls

Telemedicine with nonmydriatic cameras can detect not only diabetic retinopathy but also other eye disease. To determine the prevalence of eye diseases detected by telemedicine in a population with a high prevalence of minority and American Indian/Alaskan Native (AI/AN) ethnicities. We recruited diabetic patients 18 years and older and used telemedicine with nonmydriatic cameras to detect eye disease. Two trained readers graded the images for diabetic retinopathy, age-related macular degeneration (ARMD), glaucomatous features, macular edema, and other eye disease using a standard protocol. We included both eyes for analysis and excluded images that were too poor to grade. We included 820 eyes from 424 patients with 72.3% nonwhite ethnicity and 50.3% AI/AN heritage. While 283/424 (66.7%) patients had normal eye images, 120/424 (28.3%) had one disease identified; 15/424 (3.5%) had two diseases; and 6/424 (1.4%) had three diseases in one or both eyes. After diabetic retinopathy (104/424, 24.5%), the most common eye diseases were glaucomatous features (44/424, 10.4%) and dry ARMD (24/424, 5.7%). Seventeen percent (72/424, 17.0%) showed eye disease other than diabetic retinopathy. Telemedicine with nonmydriatic cameras detected diabetic retinopathy, as well as other visually significant eye disease. This suggests that a diabetic retinopathy screening program needs to detect and report other eye disease, including glaucoma and macular disease.

BackgroundUndiagnosed ocular diseases and ocular complications from systemic diseases are common in primary care populations, and many can be detected through retinal imaging before symptoms develop. Asynchronous store-and-forward teleophthalmology offers a scalable way to integrate eye screening into primary care, yet its broader impact beyond diabetes and diabetic retinopathy detection remains underexplored.ObjectiveThis study evaluated the outcomes of asynchronous store-and-forward teleophthalmology screening in a primary care clinic, including detection and triage of ocular conditions and subsequent changes in eye and systemic management.MethodsThis was a retrospective cross-sectional analysis of the first 200 patients screened in a single primary care clinic in Elmhurst, New York, between January and May 2025. Each patient underwent nonmydriatic external and posterior eye imaging, which was reviewed by a remote reading eye clinician. Reports included eye findings, triage decisions (routine monitoring vs in-person referral), and management recommendations. Subsequent changes in care were extracted from primary care and in-person specialist consult notes.ResultsOf 200 patients (mean age 62.1, SD 19.0, range 11‐100 years), 71.5% (143/200, 95% CI 64.9-77.3) had positive eye findings, and 40% (80/200, 95% CI 33.5‐46.9) were referred for in-person eye examinations. Only 8.8% (7/80, 95% CI 4.3-17.0) of referrals were for diabetic retinopathy; most were for glaucoma suspects, age-related macular degeneration, cataracts, and other eye diseases. Image quality was high, with 98.2% (390/397, 95% CI 96.4-99.1) of fundus images being at least partially adequate. Of the 32 patients with documented in-person eye follow-up, 87.5% (28/32) of evaluations confirmed the screening findings. Eye management changes were initiated in 11 patients, whereas systemic management changes occurred in 70 patients, including new prescriptions for Age-Related Eye Disease Study 2 supplements, antihypertensives, diabetes medications, and lipid-lowering agents.ConclusionsAsynchronous teleophthalmology screening in a primary care setting effectively identified both ocular diseases and ocular complications from systemic diseases, leading to meaningful changes in eye and systemic management. The low rate of diabetic retinopathy among referrals highlights the broader diagnostic value of retinal imaging beyond diabetes management. This care model offers a scalable, high-yield strategy for proactive disease detection and interdisciplinary intervention at the primary care level.

ABSTRACTIntroduction: Drug delivery to the back of the eye requires strategic approaches that guarantee the long-term therapeutic effect with patient compliance. Current treatments for posterior eye diseases suffer from significant challenges including frequent intraocular injections of anti-VEGF agents and related adverse effects in addition to the high cost of the therapy.Areas covered: Treatment challenges and promising drug delivery approaches for posterior segment eye diseases, such as age-related macular degeneration (AMD) are summarized. Advances in the development of several nanotechnology-based systems, including stimuli-responsive approaches to enhance drug bioavailability and overcome existing barriers for effective ocular delivery are discussed. Stem cell transplantation and encapsulated cell technology (ECT) approaches to treat posterior eye diseases are elaborated.Expert opinion: There are several drug delivery systems demonstrating promising results. However, a better understanding of ocular barriers, disease pathophysiology, and drug clearance mechanisms is required for better therapeutic outcomes. The stem cell transplantation strategy and ECT approach provide positive results in AMD therapy, but there are a number of challenges that must be overcome for long-term efficiency. Ultimately, there are numerous multidimensional challenges to cure vision problems and a collaborative approach among scientists is required.

Various techniques to diagnose eye diseases such as diabetic retinopathy (DR), glaucoma (GLC), and age-related macular degeneration (AMD), are possible through deep learning algorithms. A few recent studies have examined a couple of major diseases and compared them with data from healthy subjects. However, multiple major eye diseases, such as DR, GLC, and AMD, could not be detected simultaneously by computer-aided systems to date. There were just high-performance-outcome researches on a pair of healthy and eye-diseased group, besides of four categories of fundus image classification. To have a better knowledge of multi-categorical classification of fundus photographs, we used optimal residual deep neural networks and effective image preprocessing techniques, such as shrinking the region of interest, iso-luminance plane contrast-limited adaptive histogram equalization, and data augmentation. Applying these to the classification of three eye diseases from currently available public datasets, we achieved peak and average accuracies of 91.16% and 85.79%, respectively. The specificities for images from the eyes of healthy, GLC, AMD, and DR patients were 90.06%, 99.63%, 99.82%, and 91.90%, respectively. The better specificity performances may alert patient in an early stage of eye diseases to prevent vision loss. This study presents a possible occurrence of a multi-categorical deep neural network technique that can be deemed as a successful pilot study of classification for the three most-common eye diseases and can be used for future assistive devices in computer-aided clinical applications.

Purpose To estimate the prevalence of major age‐related eye diseases in a population‐based regional study in Southern Germany.Methods 822 randomly selected persons (age 68‐96 years) from the KORA AGE study were asked in 2012 in a standardized interview for the presence of major eye disorders like cataracts, glaucoma and age‐related macula degeneration (AMD). In case of any positive reply, the ophthalmologist in charge was asked for validation and specification of any eye disease.Results 465 persons reported any eye disorder (57%); 71% of them could be validated and specified. There were 182 confirmed cases of cataracts, 7 of glaucoma and 5 of AMD. Additionally, there were 52 cases of cataracts and AMD, also 54 cases of cataract and glaucoma and 11 cases of cataract, glaucoma and AMD. In 62% cases cataracts developed prior to any of the other eye diseases. Adjusted for age, women had a significantly higher risk for cataracts (OR = 1.72) and for AMD (OR = 1.94) than men; no gender‐specific difference was observed for glaucoma. Among patients with cataracts, 69% had lens surgery.Conclusion We confirmed cataracts as the major age‐related eye diseases; however, the number of glaucoma and AMD were surprisingly low. Further analyses are planned to identify risk factors and to show how eye diseases are independent risk factors for increased frailty and disability in the aged. This study was supported by the German Federal Ministry of Education and Research (BMBF) within the programme "Healthy Ageing" (FKZ 01ET1003)

Diabetic Retinopathy and Age-Related Macular Degeneration in the U.S