Background/Objectives: Neovascular age-related macular degeneration (nAMD) is a retinal disorder leading to irreversible central vision loss. The pro-re-nata (PRN) treatment for nAMD involves frequent intravitreal injections of anti-VEGF medications, placing a burden on patients and healthcare systems. Predicting injections needs at each monitoring session could optimize treatment outcomes and reduce unnecessary interventions. Methods: To achieve these aims, machine learning (ML) models were evaluated using different combinations of clinical variables, including retinal thickness and volume, best-corrected visual acuity, and features derived from macular optical coherence tomography (OCT). A “Leave Some Subjects Out” (LSSO) nested cross-validation approach ensured robust evaluation. Moreover, the SHapley Additive exPlanations (SHAP) analysis was employed to quantify the contribution of each feature to model predictions. Results: Results demonstrated that models incorporating both structural and functional features achieved high classification accuracy in predicting injection necessity (AUC = 0.747 ± 0.046, MCC = 0.541 ± 0.073). Moreover, the explainability analysis identified as key predictors both subretinal and intraretinal fluid, alongside central retinal thickness. Conclusions: These findings suggest that session-by-session prediction of injection needs in nAMD patients is feasible, even without processing the entire OCT image. The proposed ML framework has the potential to be integrated into routine clinical workflows, thereby optimizing nAMD therapeutic management.

Background: The melanocortin-1 receptor (MC1R) gene is a major determinant of skin and hair color. Although several MC1R variants increase the risk of skin tumors regardless of pigmentation, their role as genetic modifiers in ocular diseases remains poorly understood. Methods: Here, we analyzed a cohort of 48 Caucasian individuals using a custom next-generation sequencing (NGS) panel targeted for oculocutaneous disorders. Results: MC1R variants were identified in two probands selected from this cohort, exhibiting distinctly divergent pathological phenotypes. The first patient, an adult male with a pheomelanin-related trait and a history of early-onset skin cancer without ocular abnormalities, carried compound heterozygous MC1R variants: the novel frameshift c.537dupC (p.Ile180Hisfs*59) and the known c.880G>C (p.Asp294His). Conversely, the second patient, a young boy with severe vision-threatening features—including congenital nystagmus, foveal hypoplasia, and an atypical visual-pathway misrouting pattern—carried a candidate digenic genotype combining the same MC1R c.880G>C variant with the albinism-related c.1209G>T (p.Arg403Ser) variant in the tyrosinase (TYR) gene. Conclusions: While MC1R variants have previously been proposed as phenotypic modifiers in albinism, primarily in combination with the oculocutaneous type II melanosomal transmembrane protein (OCA2) encoding gene, our findings support a potential role for MC1R as a candidate modifier interacting with TYR in neuroretinal development. Although functional validation is required to establish causality, incorporating MC1R screening in patients with unresolved foveal hypoplasia may help clarify complex oligogenic mechanisms and optimize phenotypic classification.

Ectrodactyly–ectodermal dysplasia-clefting (EEC) syndrome is a rare genetic disorder characterized by dominant-negative mutations in the TP63 gene, leading to ectodermal and limb malformations and premature senescence of epithelial structures, particularly the corneal epithelium. This causes progressive epithelial degeneration, often resulting in limbal stem cell deficiency (LSCD) and blindness. Currently, no curative treatments exist, underscoring the need for long-lasting therapeutic strategies aimed at preservation and functional restoration of epithelial stem cells. This study provides a proof of concept for a combined gene and stem cell therapy approach to correct TP63-related disorders through the transplantation of autologous, genetically modified keratinocyte stem cells. We engineered a self-inactivating (SIN) lentiviral vector expressing ΔNp63α-EGFP under the control of the epithelial-specific K14 regulatory elements to achieve physiological, lineage-restricted expression of wild-type ΔNp63α in oral mucosa epithelial stem cells (OMESCs). Transduced mutant cells were evaluated alongside wild-type controls through lifespan assays, colony-forming efficiency (CFE) assays, confocal microscopy, qPCR, and organotypic 3D cultures. Transgene expression was selectively activated in p63-positive epithelial progenitor cells, confirming the tissue specificity of the K14 enhancer. This led to an extended proliferative lifespan and improved clonogenic potential while maintaining cell stratification capability. Integration site analysis revealed an integration profile consistent with that expected for SIN lentiviral vectors. These results support the feasibility of a mutation-independent gene addition strategy to restore ΔNp63α function in epithelial stem cells through tight transcriptional regulation, thereby minimizing off-target effects. Overall, this approach offers a promising therapeutic platform for the long-term correction of TP63-related disorders, particularly for ocular surface reconstruction in patients with EEC syndrome.

Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is a rare genetic disorder characterized by dominant-negative mutations in the TP63 gene, leading to ectodermal and limb malformations and premature senescence of epithelial structures, particularly the corneal epithelium. This causes progressive epithelial degeneration, often resulting in limbal stem cell deficiency (LSCD) and blindness. Currently, no curative treatments exist, underscoring the need for long-lasting therapeutic strategies aimed at preservation and functional restoration of epithelial stem cells. This study provides proof of concept for a combined gene and stem cell therapy approach to correct TP63-related disorders through the transplantation of autologous, genetically modified keratinocyte stem cells. We engineered a self-inactivating (SIN) lentiviral vector expressing ΔNp63α-EGFP under the control of the epithelial-specific K14 regulatory elements to achieve physiological, lineage-restricted expression of wild-type ΔNp63α in oral mucosa epithelial stem cells (OMESCs). Transduced mutant cells were evaluated alongside wild-type controls through lifespan assays, colony-forming efficiency (CFE) assays, confocal microscopy, qPCR, and organotypic 3D cultures. Transgene expression was selectively activated in p63-positive epithelial progenitor cells, confirming the tissue specificity of the K14 enhancer. This led to an extended proliferative lifespan and improved clonogenic potential while maintaining cell stratification capability. Integration site analysis revelaed an integration profile consistent with that expected for SIN lentiviral vectors. These results support the feasibility of a mutation-independent gene addition strategy to restore ΔNp63α function in epithelial stem cells through tight transcriptional regulation, thereby minimizing off-target effects. Overall, this approach offers a promising therapeutic platform for the long-term correction of TP63-related disorders, particularly for ocular surface reconstruction in patients with EEC syndrome.

Background: Symptomatic vitreous floaters are generally considered benign and self-limiting, especially in young individuals. However, persistent symptoms can sig-nificantly impair vision and quality of life, even when best-corrected visual acuity (BCVA) is preserved. Long-term data on pars plana vitrectomy (PPV) for floaters in young patients remain limited. Methods: This retrospective observational study included patients under 50 years old affected by persistent symptomatic vitreous floaters for at least 24 months who underwent PPV over 10 years at a single tertiary referral center. All eyes had undergone a stand-ardized 25-gauge vitrectomy. If posterior vitreous detachment (PVD) was absent, it was induced. Next, the vitreous base was shaved, the peripheral retina was inspected, and endolaser was applied as indicated. Air tamponade was used at the surgeon’s discretion and was always applied for retinal breaks. Results: Eighty-nine eyes were included. Mean age at surgery was 37.0 ± 7.0 years, with 59.6% of patients under 40 years old. The median duration of symptoms before surgery was 32 months (27–48). Preoperative BCVA was preserved in almost all eyes and re-mained stable postoperatively, with a mean change of +0.03 logMAR. The median fol-low-up was 60 months (58–72). No cases of rhegmatogenous retinal detachment, new-onset glaucoma, or visually significant cataract needing surgery were observed. Postoperative complications included endophthalmitis in one eye, macular hole in one eye, and permanent visual field defects in two eyes due to optic nerve touch during PVD induction. Importantly, no eye required reintervention for recurrent symptomatic floaters. Conclusions: Symptomatic vitreous floaters may persist for years in some young patients. Surgery may be considered when symptoms are significant. In this series, complete PPV with PVD induction provided stable BCVA and anatomical outcomes, with no reinter-vention for recurrent visually disturbing floaters. However, serious complications show that this elective procedure carries real risks.