Multifunctional macrophage membrane biomimetic nanoparticles for targeted therapy of neovascular age-related macular degeneration.

Background/Objectives: Oxidative stress plays a significant role in the development and progression of age-related macular degeneration (AMD). Retinal pigment epithelium (RPE) cells are specialized multifunctional cells indispensable for the maintenance of vision. The dysfunction and death of RPE cells in the macula characterize the onset and development of AMD. Of the various toxic agents that impact the health of the RPE, particular focus has been given to various forms of lipoproteins and their cytotoxic derivatives normally present in the retina. Oxidized low-density lipoprotein (OxLDL), derived from LDL in a pro-oxidative environment, is found adjacent to RPE cells as part of drusen, extracellular deposits that are a hallmark feature of AMD. OxLDL is a potent inflammatory agent and it has been implicated in cardiovascular and neurodegenerative conditions. The cellular molecular mechanisms triggered by OxLDL are only partially understood. The focus of this study was to characterize changes in the proteome of RPE cells after exposure to OxLDL, with a focus on the characterization and quantification of ubiquitinated proteins. Methods: Identification and quantification were performed with a high-resolution LC-MS/MS-based proteomics workflow after immune-enrichment for ubiquitinated peptides. Results: In total, out of the more than 1000 RPE ubiquitinated peptides quantified, OxLDL treatment caused a significant increase in ubiquitinated peptides compared to LDL and untreated cells. Principal component analysis (PCA) of the differentially ubiquitinated proteins (265) reduced the data complexity in two main groups of variables (proteins). Conclusions: Gene ontology enrichment analysis of the grouped proteins with the highest loading contribution to principal component 1 (PC1) and principal component 2 (PC2) revealed significant ubiquitination changes upon OxLDL treatment in proteins of the ubiquitin–proteasome system (UPS) responsible for proteasome-mediated catabolic processes and in protein members of the cellular translation machinery.

No current treatments are curative for age-related macular degeneration (AMD), and preventing disease progression is challenging. Dietary factors play a role in the course of macular degeneration, and management of AMD commonly includes nutraceuticals (e.g., supplementation with a combination of antioxidant vitamins and minerals). This commentary summarizes the existing literature, emerging evidence, and upcoming research on the role of Bvitamins in both preventing the development of AMD and slowing its progression.

Retinal diseases like age-related macular degeneration (AMD), diabetic retinopathy (DR), and diabetic macular edema (DME), alongside optic neuropathies such as glaucoma, are primary contributors to irreversible visual impairment and blindness, and not only impact the quality of life but also place considerable socioeconomic pressures on healthcare systems worldwide. Despite the availability of several therapeutic modalities, the clinical management of these conditions remains challenging due to the unique anatomical and physiological barriers of the eye (i.e., tear film, cornea, blood-aqueous barrier, and the blood-retinal barrier), which impede achieving therapeutic drug concentrations in the posterior segment. Topical administration exhibits low bioavailability, while systemic delivery is generally inefficient and associated with adverse effects. Intravitreal injections (IVIs) deliver drugs directly to the vitreous but necessitate frequent administration, hence increasing risks of endophthalmitis, retinal detachment, and patient non-compliance. Nanomedicine has revolutionized drug delivery science across various medical fields, offering significant advantages for therapeutic interventions. Nanoparticle (NP)-based systems enhance drug solubility and stability, improve pharmacokinetic profiles, facilitate passage across biological barriers, and enable targeted delivery to specific cells or tissues with surface modifications, thereby potentially increasing bioavailability while minimizing systemic toxicity. This review aims to illustrate recent advancements in the design principles, preclinical applications, and translational potential of NP-based drug delivery systems aimed at addressing the challenges inherent in treating posterior segment eye diseases. NPs (ranging from polymeric and lipid-based systems to inorganic and hybrid forms) have been able to effectively carry various formulations of antiangiogenic, anti-inflammatory, anti-neoplastic, and antioxidant compounds, as well as genetic materials, to counteract such disorders. NP's size, surface charge, and composition can be modulated to optimize interaction with ocular tissues and overcome barriers. With their controlled and sustained drug release, NPs decrease the required frequency of IVIs. In addition, NPs can encapsulate a wide range of therapeutic agents (including hydrophobic molecules, proteins, and nucleic acids) and are amenable to the functionalization of their surfaces with ligands for specific receptors on retinal cells, thereby enhancing therapeutic efficacy and minimizing local toxicities. The findings of this review will establish a research agenda for translating NP-based interventions into clinical practice.

To investigate associations between systemic complement activation and choroidal thickness (CT) in advanced non-neovascular age-related macular degeneration (nnAMD). Cross-sectional study of 96 patients (187 eyes) with advanced nnAMD enrolled in the University of Colorado AMD Registry (August 2014-June 2021). Medical histories, multimodal imaging, and plasma samples were collected. Plasma was analyzed via enzyme-linked immunosorbent assay and multiplex Luminex assays for complement factors C1q, monoclonal B-cell lymphocytosis, C2, C4, C4b, C3, C3a, Factor B, Bb, Factor D, Factor H, Factor I, C5 and soluble C5b-9. CT was measured subfoveally and at 1000μm intervals superiorly, inferiorly, nasally, and temporally using Spectralis OCT. Linear modeling with generalized estimating equations assessed log-transformed OCT and complement factors. The mean age was 82.2 years (± 7.1 SD); 54.2% were female. Average CT was negatively associated with Bb (β=-0.47, SE: 0.12, p = 0.0001) and the Bb/Factor B ratio (β=-0.28, SE: 0.12, p = 0.02), but not other complement markers. Bb levels correlated with alternative pathway components but not with classical or lectin pathway markers. We found a key association between systemic complement activation of Factor B and choroidal thickness in patients with advanced nnAMD, implying the potential involvement of the systemic alternative pathway in nnAMD patients.

To determine whether handgrip strength is associated with the incidence of age-related macular degeneration. A prospective cohort study of over 500 thousand UK Biobank participants aged 40-69 years. Individuals ≥ 50 years and without age-related macular degeneration at baseline were included. Exposure was the handgrip strength measured by dynamometer. Primary outcome was the incidence of age-related macular degeneration during 13 years of follow-up. Cox proportional-hazard models were fitted to estimate the risk effect for handgrip strength on age-related macular degeneration, and stratified for sociodemographic and lifestyle factors. Mediation models were regressed to explore underlying mechanisms driven by inflammatory and erythrocyte-related biomarkers. 382174 eligible participants in the UK Biobank were included. After 4680431 person-year, 7987 individuals (2.09%) developed age-related macular degeneration. Individuals in the lowest quintile of handgrip strength had higher risk of age-related macular degeneration incidence (Hazard Ratio, 1.25; 95% CI, 1.16-1.35) compared with those in the highest quintile. Per 5kg decrement in handgrip strength was associated with increased risk of age-related macular degeneration incidence (Hazard Ratio, 1.06; 95% CI, 1.04-1.08) with similar trend among all subgroups except for sex. Specific inflammatory and erythrocyte-related biomarkers partially (37.5%) mediated the incidence of age-related macular degeneration as substantial biological mechanisms following handgrip strength decrease. Our findings suggest that handgrip strength is associated with the incidence of age-related macular degeneration under the mediation of systemic proinflammatory factors. The current study holds an outlook for improved visual health over the evaluation and intervention of muscle strength in old-age population.

To provide a comprehensive overview of the structural and functional characteristics of the blood-retinal barrier (BRB), examine its critical role in the pathogenesis of major ocular diseases, and summarize current and emerging therapeutic strategies aimed at restoring BRB integrity. A literature search was conducted in PubMed, Scopus, and Web of Science databases, focusing primarily on publications from the past 10 years supplemented by seminal earlier works. This narrative review synthesizes evidence on BRB molecular anatomy, pathological mechanisms, disease-specific roles, and therapeutic interventions. The BRB comprises inner (iBRB) and outer (oBRB) compartments with distinct cellular and molecular architectures. BRB dysfunction is driven by convergent mechanisms including aging, hyperglycemia, oxidative stress, inflammation, and hypoxia, which disrupt tight junction proteins and promote aberrant angiogenesis. This barrier breakdown constitutes a pivotal pathogenic driver in major blinding diseases: age-related macular degeneration, diabetic retinopathy and retinal vein occlusion, glaucoma, and uveitis. Current standard treatments include anti-VEGF agents and corticosteroids. Emerging strategies target Wnt/β-catenin signaling, employ senolytic therapies, utilize biomaterial-based drug delivery, and develop organ-on-a-chip models for personalized medicine. BRB disruption represents a critical inflection point in ocular disease progression, triggering self-perpetuating cycles of neuroinflammation and degeneration. Effective restoration requires multi-faceted approaches combining anti-angiogenic, antiinflammatory, and barrier-strengthening mechanisms. Future research should focus on dynamic functional assessment, single-cell multi-omics integration, and adaptive therapeutic strategies to prevent irreversible vision loss.

Sense organ diseases represent the leading causes of years lived with disability. Despite its major impact, a comprehensive understanding of sense organ diseases burden remains limited. Based on the data from the Global Burden of Disease Study 2021 and nighttime light exposure data from remote-sensing satellites, we did secondary analysis and described the epidemiological characteristics of sense organ diseases globally and nationally. The relationship between the specific causes of blindness and vision loss and nighttime light exposure was further explored. We assessed the trends, causes and cross-country inequalities related to sense organ diseases and forecasted the burden of disease until 2050. Here we show that in 2021, there are more than 2 billion prevalent cases and more than 77 million years lived with disability cases of sense organ diseases globally. Both age-related macular degeneration and near vision loss show positive correlations with nighttime light exposure. The global burden of sense organ diseases continues to rise from 1990 to 2021, primarily driven by population growth and ageing. Health inequalities exist between different countries and increase over time. Projections of years lived with disability for sense organ diseases from 2022 to 2050 show that although the age-standardized rate remains stable, the number increases significantly. Over the past 32 years, the global burden of sense organ diseases has increased, and cross-country inequalities have intensified due to the trends of population growth and aging. Therefore, it is urgently necessary to formulate more targeted and effective prevention and management strategies.

To evaluate the clinical outcomes of the switch to faricimab in a treat-and-extend (T&E) regimen patients with neovascular age-related macular degeneration (nAMD). This prospective cohort study included consecutive patients with nAMD who had previously been treated with anti-VEGF agents in a T&E regimen, with treatment intervals (TI) that could not be extended beyond 12 weeks, and a minimum follow-up of 24 weeks. These patients were switched to faricimab therapy in a T&E regimen for at least 6 months. The primary endpoint was the TI between intravitreal injections (IVIs), and the secondary endpoint was the mean change in best-corrected visual acuity (BCVA) from baseline to the last follow-up visit (LFUV). A total of 225 eyes from 188 patients were included, with a mean age of 79.6 ± 7.4 years. Previous anti-VEGF treatments included ranibizumab (n = 34), aflibercept (n = 144), brolucizumab (n = 6), and bevacizumab (n = 41). TI1 (5.9 ± 2.0 weeks) matched the prior treatment interval. Significant increases in treatment intervals were observed at subsequent time points (TI2: 8.2 ± 3.2 weeks, TI3: 10.1 ± 3.9 weeks, TI4: 10.7 ± 4.3 weeks, TI5: 9.9 ± 4.0 weeks, and TI6: 8.5 ± 4.4 weeks; p < 0.001). BCVA remained stable, going from 0.41 ± 0.23 to 0.43 ± 0.24 (p = 0.0112). The mean number of injections was 5.9 ± 1.9, with a mean follow-up duration of 51.4 ± 11.8 weeks. The switch to faricimab in a T&E regimen significantly increased treatment intervals maintaining BCVA in patients with nAMD under other anti-VEGF treatments. No serious adverse events were reported. Longer follow-up is needed to confirm these results.

PurposeTo analyze choroidal thickness (CT) in patients with neovascular age-related macular degeneration (nAMD) with type 1 macular neovascularization (MNV) and type 3 (or retinal angiomatous proliferation) after antiVEGF treatment for two years.MethodsRetrospective study enrolling Caucasian naïve patients with nAMD (type 1 MNV), and patients with type 3 MNV with no other ophthalmological disorders, and without switching treatment. Nine manual CT measurements were performed on optical coherence tomography (OCT) Spectralis (Heidelberg Engineering). Demographic data, smoking, disease activity, and number of injections, among others were recorded. Three visits were analyzed: pretreatment baseline visit, first and last visits with no disease activity.Results53 eyes of 53 patients with type 1 MNV, and 41 eyes of 41patients with type 3 MNV were analyzed. Both groups received the same number of injections (p = 0.282). Type 3 MNV patients showed lower CT (between 143.29 and 174.17μm) than type 1 MNV patients (between 169.91 and 220.17μm) in the baseline visit, but differences disappeared in first and last visits. Choroidal thinning was only observed in type 1 MNV patients between baseline and first visit (p < 0.05). In the las visit, they had a CT between 87 and 96% of baseline measurement. No other influencing factor was detected.ConclusionsPatients with nAMD (type 1 MNV) have higher CT than patients with type 3. However, patients with type 1 MNV experience significant choroidal thinning, and CT is similar in both groups after antiVEGF treatment. Smoking, type of drusen or other OCT features have no influence in this reduction.

PurposeThis study aimed to investigate the conjunctival microbiota of patients requiring intravitreal injections due to diabetic retinopathy (DR), age-related macular degeneration (AMD), and retinal vein occlusion (RVO).MethodsA total of 182 participants (46 DR, 71 AMD, 16 RVO, and 49 controls) were enrolled between August and November 2024. Conjunctival swabs were collected from both eyes under sterile conditions prior to injection and cultured on 5% sheep blood and chocolate agar. Microorganisms were identified using Vitek MS.ResultsNo significant differences were observed among the groups in overall microbial growth frequency (all p > 0.05). Gram-negative bacteria, fungi, and polymicrobial growth were more frequently detected in DR and AMD patients, suggesting a trend toward greater microbial diversity, although these differences were not statistically significant.ConclusionDR and AMD patients exhibited higher prevalence of gram-negative, fungal, and polymicrobial colonization. These findings underscore the importance of strict aseptic preparation, povidone-iodine disinfection, and targeted prophylactic strategies to minimize post-injection infection risk in high-risk populations.

Little is known about whether and to what degree people with different amounts of visual impairment rely on hearing instead of vision for mobility, particularly in judgments of collision. We measured how much importance was assigned to visual and auditory cues during time-to-collision judgments made by people with age-related macular degeneration (Impaired Vision Group; IV) compared to a control group without age-related macular degeneration (Normal Vision Group; NV). A virtual reality system simulated a roadway with an approaching vehicle viewed from the perspective of a pedestrian. Participants pressed a button to indicate the time the vehicle would reach them. The vehicle was presented visually only, aurally only, or both simultaneously. Standardized regression coefficients and general dominance weights indicated that time-to-collision (TTC) judgments were determined by both auditory and visual cues in both groups. In the vision-only modality condition, the relative importance of distance and optical size compared to TTC was higher in the IV group compared to the NV group, but with a relatively small effect size. In all modality conditions, the mean absolute error of TTC estimates was comparable between groups, and a multimodal advantage was not observed. Intraindividual variability was greater in the IV group only in the AV condition. The implication is that similar performance can be achieved through the use of different sources of information. Importantly, people with and without IV achieved similar performance but showed differences in the relative importance of different sensory sources of information. A comparison of two IV subgroups differing in severity suggested that simply having IV in both eyes is not sufficient to predict TTC estimation differences between people with IV and people without IV who have normal vision. Rather it appears to be the degree of bilateral visual impairment of the IV that matters.

Inherited retinal diseases (IRDs) are rare and diverse, posing a diagnostic challenge in ophthalmology. This study aimed to determine whether artificial intelligence (AI)-assisted image processing can improve IRD diagnosis and provide insights into disease characteristics. We used an optical coherence tomography (OCT) segmentation algorithm to characterize retinal features in IRDs. Two control groups were included to enhance the contextual understanding of these features: healthy eyes and eyes with age-related macular degeneration (AMD). An AI-driven classification model was then used to classify the data into disease and control groups. We analyzed 327 images from 181 patients with IRD and 146 control individuals, including healthy subjects and patients with AMD. IRD cases were stratified into macular and retinal dystrophies. Automated segmentation of six retinal layers and detection of nine biomarkers were performed on retinal OCT images using the AI-based RetinAI Discovery tool. A random forest classifier differentiated macular IRD, retinal IRD, and controls. The model detected IRD with 91% accuracy and achieved 91% accuracy in differentiating macular from retinal IRD. Key OCT features for differentiation included reduced perifoveal photoreceptor and outer nuclear layer thicknesses and increased retinal nerve fiber layer thickness in retinal IRD. Macular IRD featured significant foveal photoreceptor and outer nuclear layer thinning. This study shows that standardized OCT image analysis combined with AI-based classification can accurately detect and stratify IRDs. The model's high accuracy highlights its potential as a reliable diagnostic tool in ophthalmology. This AI-assisted OCT evaluation approach enhances ophthalmic diagnostics by improving IRD detection and classification.

The technique of 2‑photon microperimetry is an emerging procedure that combines measurement of retinal sensitivity with retinal imaging and offers substantial improvements compared to conventional microperimetry. Conventional microperimetry relies on 1‑photon linear absorption while 2‑photon microperimetry relies on the simultaneous absorption of two photons, leading to enough energy for photoisomerization of visual pigments and perception of colors, such as green. This 2‑photon absorption process has shown alower spread of measurements at one retinal location, leading to more reproducible data compared to conventional microperimetry. The current literature also suggests that 2‑photon microperimetry provides more reliable measurements in the presence of lens opacities, acommon issue in an aging eye. Furthermore, it has been successfully utilized to assess retinal function in patients with diabetic retinopathy, age-related macular degeneration and glaucomatous neuropathy. These advantages highlight the very promising application in clinical settings. Future adjustments focusing on implementing this technology in the clinical practice could improve outcomes in the early detection and monitoring of retinal diseases.

Abstract—Retinal diseases like diabetic retinopathy, age-related macular degeneration, and glaucoma cause widespread vision loss, but early detection is limited by specialist shortages. This paper introduces a web-based system using fine-tuned ResNet50 for multi-class retinal disease classification from fundus images. Built with HTML/CSS/JavaScript (Tailwind CSS) frontend, Flask/Python backend, PostgreSQL and TensorFlow with OpenCV preprocessing, it enables secure image uploads and real-time predictions. Experiments on datasets like APTOS achieve 92% accuracy, outperforming baselines in precision, recall, and F1-score. The system supports scalable deployment in underserved areas, reducing diagnostic delays and aiding blindness prevention. Key Words: Retinal disease detection, ResNet50, deep learning, fundus images, Flask web application, TensorFlow, diabetic retinopathy, PostgreSQL, image classification

ABSTRACTGeographic atrophy (GA) is characterized by the loss of choriocapillaris, retinal pigment epithelium (RPE) and photoreceptors and is an advanced form of age‐related macular degeneration (AMD)–a leading cause of central vision loss in the elderly. The development of effective treatments has been hindered by the lack of reliable animal models that recapitulate the structural, functional, and molecular hallmarks of GA. In this study, we established and extensively characterized a sodium iodate (NaIO3)‐induced model of GA in pigmented Long Evans rats using a comprehensive set of in vivo and histological techniques. NaIO3 was administered intraperitoneally at 80 mg/kg to induce bilateral retinal degeneration. Morphological, functional, and ultrastructural changes were evaluated using scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), electroretinography (ERG), light and electron microscopy, and immunohistochemistry at pre‐dose and 3, 7, and 14 days post‐injection. The model exhibited typical GA features including choriocapillaris loss, RPE degeneration, photoreceptor death, Bruch's membrane remodeling, and mitochondrial damage. Complement activation (C3, C5b‐9) and immune cell infiltration (Iba1, CD68) were observed, along with gliosis and RPE65 loss. ERG analysis revealed profound and persistent functional deficits. These findings demonstrate that the NaIO3 rat model robustly mimics the key pathological events in GA, particularly at 7 days post‐injection, making it a suitable model for preclinical evaluation of therapeutic interventions targeting choriocapillaris and RPE protection.

The purpose of this study was to determine the safety and feasibility of fluorescence molecular imaging using a commercially available system and intravenous injection of fluorescently labeled bevacizumab (bevacizumab-800CW) to visualize bevacizumab distribution in patients with neovascular age-related macular degeneration (nAMD)s. Methods: Twelve patients with active nAMD aged 60 y or older, who were either on anti-vascular endothelial growth factor (VEGF) therapy or were anti-VEGF therapy naïve, received an intravenous injection of 4.5 mg (n = 3) or 15 mg (n = 9) of bevacizumab-800CW. This clinical trial was divided into 2 parts. An interim analysis was performed after the inclusion of 3 patients per dose group (study part 1) to determine the more optimal dose. Then 6 additional patients were included with the optimal dose in study part 2. All patients underwent standard clinical imaging, including fundus photography, optical coherence tomography, optical coherence tomography angiography, and fluorescein angiography. Fluorescence imaging was performed 1 min, 60 min, and 3-4 d after bevacizumab-800CW injection. Results: Bevacizumab-800CW injections were safe and well tolerated. One minute after injection, only the 15-mg group demonstrated a significantly higher contrast-to-noise ratio (median, 6.32) in vessels compared with baseline (median, -4.44; P = 0.0342). This, combined with the clear visual uptake after 3-4 d, supported 15 mg as the preferred dose. Contrast-to-noise ratio values inside the macula of patients receiving 15 mg of bevacizumab-800CW (n = 8) were significantly higher after 3-4 d (median, 4.45) compared with baseline (median, 0.19; P = 0.0078). Conclusion: Targeted fluorescent tracers such as bevacizumab-800CW can visualize VEGF expression, providing important insights into nAMD, and can pave the way toward personalized treatments and targeted drug development.

BackgroundVolatile organic compounds (VOCs), commonly emitted from vehicle exhaust and industrial activities, are prevalent air pollutants in urban environments. These compounds have been reported to cause various health effects through mechanisms such as oxidative stress and neurotoxicity. Recently, air pollution has attracted attention as a potential risk factor for age-related macular degeneration (AMD); however, the association between VOC exposure and AMD remains unclear.ObjectiveThis study aimed to assess VOC exposure levels among urban-dwelling AMD patients by quantifying urinary metabolites and investigating the association between VOCs and AMD.MethodsThis cross-sectional study included 40 untreated AMD patients (AMD group), 10 cataract patients (Cataract group), and 10 healthy controls (Healthy group). Representative urinary metabolites of VOCs—2-methylhippuric acid, 3-methylhippuric acid, mandelic acid, phenylglyoxylic acid, and trans,trans-muconic acid—were measured using gas chromatography-mass spectrometry (GC/MS), with concentrations corrected for urinary creatinine. Group comparisons were performed based on creatinine-adjusted metabolite levels.ResultsThe AMD group exhibited elevated urinary VOC metabolite levels compared to both control groups. The ratios of mean concentrations in the AMD group versus the Healthy and Cataract groups, respectively, were: 2-methylhippuric acid (201% and 181%), 3-methylhippuric acid (190% and 139%), mandelic acid (304% and 198%), phenylglyoxylic acid (118% and 90%), and trans,trans-muconic acid (214% and 92%). Among these, 2-methylhippuric acid and mandelic acid were significantly higher in the AMD group than in both controls (p < 0.001 and p = 0.042; p < 0.001, respectively). Trans,trans-muconic acid also showed a significant increase compared to the Healthy group (p < 0.001). Correlation analysis within the AMD group revealed moderate but significant associations for 2-methylhippuric acid (r = 0.29, p = 0.011), mandelic acid (r = 0.47, p < 0.001), and trans,trans-muconic acid (r = 0.27, p = 0.020). Multivariate logistic regression identified mandelic acid as an independent factor significantly associated with AMD (odds ratio = 17.20, p < 0.001). Subgroup analysis categorized the AMD group into drusenoid AMD, typical AMD (t-AMD), polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP). No significant differences in urinary VOC metabolite levels were observed among the four subtypes after multiple comparison adjustment.ConclusionsThese findings indicate that AMD patients are exposed to higher levels of traffic-related VOCs. While mandelic acid—a styrene metabolite—was independently associated with AMD, its role should be interpreted as a potential exposure marker rather than a definitive disease biomarker. Further longitudinal studies are warranted to clarify causal relationships between VOC exposure and AMD development.

ABSTRACTPhotoreceptor transplantation is being studied to restore visual function in retinal diseases causing blindness, including age‐related macular degeneration, hereditary eye diseases, and traumatic retinopathy. Preclinical studies often involve delivering exogenous human photoreceptor cells into animal models' retinas. A key readout in such experiments is distinguishing donor cell integration from artificial labeling secondary to material transfer of cytosolic or nuclear labels. Recognizing donor (human) versus animal photoreceptor nuclei is key, but purely immunohistology discrimination is challenging due to antigenic species overlap or intercellular antigen transfer. To address this, we sought to develop and validate a computational technique to discriminate between photoreceptor cells of different animal species based on machine learning of nuclear morphology. We aim to evaluate the feasibility of computer‐assisted nuclear detection combined with random forest classification to automate species differentiation in DAPI‐stained photoreceptors after xenotransplantation into mouse and pig retinas. Our models were trained on single‐species samples and validated with mixed‐species samples. We then transplanted human embryonic stem cell‐derived retinal organoid cells into rodent and pig retinal degeneration models. The random forest model accurately determined cell identity post‐xenotransplantation, validated by histological assessment using an antihuman nuclear antibody. Our results support the potential efficacy of employing machine learning image analysis and classification techniques that may promote experimental rigor, minimize observer bias, and enable high throughput semiautomated workflows for transplantation outcomes analysis. The methodological framework reported here may enable a more nuanced and precise analysis of the behavior of transplanted photoreceptors for the purposes of human retinal regeneration.

Elamipretide (Forzinity™) is a mitochondrial cardiolipin binder being developed by Stealth BioTherapeutics for the treatment of a range of disorders featuring mitochondrial dysfunction. In September 2025, elamipretide was granted accelerated approval in the USA for use to improve muscle strength in adult and pediatric patients with Barth syndrome weighing ≥30kg. With this accelerated approval, elamipretide became the first disease-specific treatment approved for Barth syndrome, an ultra-rare X-linked recessive genetic disorder. Elamipretide is also under phaseIII clinical development for use in the treatment of dry age-related macular degeneration and mitochondrial myopathies. This article summarizes the milestones in the development of elamipretide leading to this first approval for Barth syndrome.