Increased Anti-Inflammatory Therapeutic Potential and Progenitor Marker Expression of Corneal Mesenchymal Stem Cells Cultured in an Optimized Propagation Medium.

There is a huge unmet need for new treatment modalities for ocular surface inflammatory disorders (OSIDs) such as dry eye disease and meibomian gland dysfunction. Mesenchymal stem cell therapies may hold the answer due to their potent immunomodulatory properties, low immunogenicity, and ability to modulate both the innate and adaptive immune response. MSC-like cells that can be isolated from the corneal stroma (C-MSCs) offer a potential new treatment strategy; however, an optimized culture medium needs to be developed to produce the ideal phenotype for use in a cell therapy to treat OSIDs. The effects of in vitro expansion of human C-MSC in a medium of M199 containing fetal bovine serum (FBS) was compared to a stem cell medium (SCM) containing knockout serum replacement (KSR) with basic fibroblast growth factor (bFGF) and human leukemia inhibitory factor (LIF), investigating viability, protein, and gene expression. Isolating populations expressing CD34 or using siRNA knockdown of CD34 were investigated. Finally, the potential of C-MSC as a cell therapy was assessed using co-culture with an in vitro corneal epithelial cell injury model and the angiogenic effects of C-MSC conditioned medium were evaluated with blood and lymph endothelial cells. Both media supported proliferation of C-MSC, with SCM increasing expression of CD34, ABCG2, PAX6, NANOG, REX1, SOX2, and THY1, supported by increased associated protein expression. Isolating cell populations expressing CD34 protein made little difference to gene expression, however, knockdown of the CD34 gene led to decreased expression of progenitor genes. C-MSC increased viability of injured corneal epithelial cells whilst decreasing levels of cytotoxicity and interleukins-6 and -8. No pro-angiogenic effect of C-MSC was seen. Culture medium can significantly influence C-MSC phenotype and culture in SCM produced a cell phenotype more suitable for further consideration as an anti-inflammatory cell therapy. C-MSC show considerable potential for development as therapies for OSIDs, acting through anti-inflammatory action.

UV light-mediated corneal crosslinking as (lymph)angioregressive pretreatment to promote graft survival after subsequent high-risk corneal transplantation (CrossCornealVision): protocol for a multicenter, randomized controlled trial.

BACKGROUND: Good vision highly depends on the transparency of the cornea, which is the "windscreen" of the eye. In fact, corneal blindness due to transparency loss is the second most common cause of blindness worldwide, and corneal transplantation is the main cure. Importantly, the cornea is normally avascular but can secondarily be invaded by pathological (blood and lymphatic) vessels due to severe inflammation, and the survival prognosis of a corneal graft mainly depends on the preoperative vascular condition of the recipient's cornea. Whereas transplants placed into avascular recipient beds enjoy long-term survival rates of > 90%, survival rates significantly decrease in pathologically pre-vascularized, so-called high-risk recipients, which account for around 10% of all performed transplants in Germany and > 75% in lower and middle-income countries worldwide. METHODS: This parallel-grouped, open-randomized, multicenter, prospective controlled exploratory investigator-initiated trial (IIT) intends to improve graft survival by preconditioning pathologically vascularized recipient corneas by (lymph)angioregressive treatment before high-risk corneal transplantation. For this purpose, corneal crosslinking (CXL) will be used, which has been shown to potently regress corneal blood and lymphatic vessels. Prior to transplantation, patients will be randomized into 2 groups: (1) CXL (intervention) or (2) no pretreatment (control). CXL will be repeated once if insufficient reduction of corneal neovascularization should be observed. All patients (both groups) will then undergo corneal transplantation. In the intervention group, remaining blood vessels will be additionally regressed using fine needle diathermy (on the day of transplantation). Afterwards, the incidence of graft rejection episodes will be evaluated for 24 months (primary endpoint). Overall graft survival, as well as regression of corneal vessels and/or recurrence, among other factors, will be analyzed (secondary endpoints). DISCUSSION: Based on preclinical and early pilot clinical evidence, we want to test the novel concept of temporary (lymph)angioregressive pretreatment of high-risk eyes by CXL to promote subsequent corneal graft survival. So far, there is no evidence-based approach to reliably improve graft survival in the high-risk corneal transplantation setting available in clinical routine. If successful, this approach will be the first to promote graft survival in high-risk transplants. It will significantly improve vision and quality of life in patients suffering from corneal blindness. TRIAL REGISTRATION: ClinicalTrials.gov NCT05870566. Registered on 22 May 2023.

Influence of Donor Factors on Descemet Membrane Endothelial Keratoplasty (DMEK) Graft Preparation Outcome.

Purpose: To determine which donor characteristics, like previous diseases and surgeries, influence the severity of the DM/endothelial lamella preparation prior to DMEK-surgery. Patients and Methods: Retrospective cross-sectional single-center study is presented. Eight hundred and forty-six eyes with DMEK-surgery between 01/2018 and 01/2021 performed at the University Hospital Cologne, Germany, were included. Information regarding the donors' previous diseases and surgeries were provided by a large database of a cornea bank (Multi Tissue Bank Mecklenburg-Vorpommern) and merged with the Cologne DMEK database, which contains information regarding preparation characteristics of the surgeon-prepared graft directly preoperatively. Three preparation groups (easy, difficult and very difficult) were correlated to the donors' previous diseases and surgeries. The following characteristics were used for the assignment in one of the three groups: stripping difficulty, rolling and staining behavior, central and peripheral adherences, tissue fragility and DM-splitting. Results: Significant risk factors for DM-splitting were diabetes mellitus (DMel) type II, heart failure, chronic kidney disease and previous cataract surgery (p=0.022, p=0.012; p=0.047 and p<0.001 respectively). Previous DMel (especially type 2) was significantly associated with the occurrence of central adherences (p=0.009). Several cardiovascular diseases (p-values between <0.001 and p=0.038), DMel type II, chronic kidney disease and previous cataract-surgery were associated with peripheral adherences (p=0.004; p=0.020 and p<0.001 respectively). Furthermore, pseudophakic donor eyes presented a higher degree of fragility of the graft (p<0.001). Age was a significant risk factor for difficult preparation (p<0.001). The staining of the graft was poorer in donors with chronic kidney disease (p=0.037). Conclusion: Donor diabetes mellitus type 2, heart failure, previous cataract surgery, chronic kidney disease and age are associated with a difficult DMEK graft preparation. For every one-year increment in donor age, the odds of having very difficult preparation were increased by 3%. Also, chronic kidney disease predisposes to a poor tissue staining with trypan blue during preparation.

A comparative study of cystoid macula edema following glaucoma drainage device surgery versus trabeculectomy.

PURPOSE: To assess and compare the risk for development of cystoid macula edema (CME) after glaucoma drainage device (GDD) implantation versus conventional trabeculectomy with mitomycin (trab) for glaucoma. METHODS: Retrospective review of consecutive patients receiving trab or GDD implantation between 2016 and 2018. Inclusion criteria were availability of pre- and postoperative spectral domain optical coherence tomography (SD-OCT) of the macula. SD-OCT images were evaluated for presence of CME qualitatively, central subfield thickness (CST) and macular volume (MV). RESULTS: 73 eyes could be included, 42 received trab and 31 GDD surgery. Eyes receiving trab on average had 0.8 ± 0.8 previous intraocular operations, while eyes with GDD implantation had 3.1 ± 1.9 (p < 0.001). Occurrence of postoperative CME was significantly more frequent after GDD implantation (6 out of 31 (19.4%)) than after trab (2 out of 42 eyes = 4.8%), (p = 0.049). Mean preoperative CST as well as MV was comparable in both groups (CST before trab: 282.7 ± 23.0 µm, CST before GDD 284.2 ± 27.3 µm, p = 0.287; MV before trab: 7.8 ± 1.1 mm3, MV before GDD: 8.0 ± 0.8mm3, p = 0.305). Mean postoperative CST and MV were significantly higher after GDD (CST 338.5 ± 129.3 µm, MV 8.8 ± 2.6 mm3) than after trabeculectomy (CST 290.6 ± 60.2 µm, p = 0.038; MV 7.8 ± 1.2mm3, p = 0.039). CONCLUSIONS: In real-life conditions, GDD surgery seems to be associated with a higher risk to develop CME when compared to conventional trabeculectomy. This information may be helpful for glaucoma surgeons to advise the patients on postoperative risks of surgery.

Allogeneic limbo-deep anterior lamellar keratoplasty (Limbo-DALK)-A novel surgical technique in corneal stromal disease and limbal stem cell deficiency.

PURPOSE: To describe a novel corneal surgical technique combining Deep Anterior Lamellar Keratoplasty (DALK) with grafting of allogeneic limbus (Limbo-DALK) for the treatment of eyes with corneal stromal pathology and limbal stem cell deficiency (LSCD). METHODS: Clinical records of six Limbo-DALKs performed in five patients diagnosed with LSCD and corneal stromal pathology requiring keratoplasty were retrospectively reviewed. All patients were diagnosed with LSCD due to various pathologies including thermal and chemical burns, congenital aniridia or chronic inflammatory ocular surface disease. Parameters analysed included demographics, diagnoses, clinical history, thickness measurements using anterior segment OCT, visual acuity, and epithelial status. Regular follow-up visits were scheduled at 6 weeks as well as 3, 6, 9, and 12 and 18 months postoperatively. Main outcome measures were time to graft epithelialisation and the occurrence of corneal endothelial decompensation. RESULTS: Two grafts showed complete epithelial closure at 2 days, two at 14 days. In one eye, complete epithelial closure was not achieved after the first Limbo-DALK, but was achieved one month after the second Limbo-DALK. No endothelial decompensation occurred except in one patient with silicone oil associated keratopathy. Endothelial graft rejection was not observed in any of the grafts. CONCLUSION: Based on the data from this pilot series, limbo-DALK appears to be a viable surgical approach for eyes with severe LSCD and corneal stromal pathology, suitable for emergency situations (e.g. corneal ulceration with impending corneal perforation), while minimising the risk of corneal endothelial decompensation.

Corneal Infantile Myofibromatosis Caused by Novel Activating Imatinib-Responsive Variants in PDGFRB.

Purpose: To investigate the genetic cause, clinical characteristics, and potential therapeutic targets of infantile corneal myofibromatosis. Design: Case series with genetic and functional in vitro analyses. Participants: Four individuals from 2 unrelated families with clinical signs of corneal myofibromatosis were investigated. Methods: Exome-based panel sequencing for platelet-derived growth factor receptor beta gene (PDGFRB) and notch homolog protein 3 gene (NOTCH3) was performed in the respective index patients. One clinically affected member of each family was tested for the pathogenic variant detected in the respective index by Sanger sequencing. Immunohistochemical staining on excised corneal tissue was conducted. Functional analysis of the individual PDGFRB variants was performed in vitro by luciferase reporter assays on transfected porcine aortic endothelial cells using tyrosine kinase inhibitors. Protein expression analysis of mutated PDGFRB was analyzed by Western blot. Main Outcome Measures: Sequencing data, immunohistochemical stainings, functional analysis of PDGFRB variants, and protein expression analysis. Results: We identified 2 novel, heterozygous gain-of-function variants in PDGFRB in 4 individuals from 2 unrelated families with corneal myofibromatosis. Immunohistochemistry demonstrated positivity for alpha-smooth muscle actin and ß-catenin, a low proliferation rate in Ki-67 (< 5%), marginal positivity for Desmin, and negative staining for Caldesmon and CD34. In all patients, recurrence of disease occurred after corneal surgery. When transfected in cultured cells, the PDGFRB variants conferred a constitutive activity to the receptor in the absence of its ligand and were sensitive to the tyrosine kinase inhibitor imatinib. The variants can both be classified as likely pathogenic regarding the American College of Medical Genetics and Genomics classification criteria. Conclusions: We describe 4 cases of corneal myofibromatosis caused by novel PDGFRB variants with autosomal dominant transmission. Imatinib sensitivity in vitro suggests perspectives for targeted therapy preventing recurrences in the future. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The role of lymphatic vessels in corneal fluid homeostasis and wound healing.

The cornea, essential for vision, is normally avascular, transparent, and immune-privileged. However, injuries or infections can break this privilege, allowing blood and lymphatic vessels to invade, potentially impairing vision and causing immune responses. This review explores the complex role of corneal lymphangiogenesis in health and diseases. Traditionally, the cornea was considered devoid of lymphatic vessels, a phenomenon known as "corneal (lymph)angiogenic privilege." Recent advances in molecular markers have enabled the discovery of lymphatic vessels in the cornea under certain conditions. Several molecules contribute to preserving both immune and lymphangiogenic privileges. Lymphangiogenesis, primarily driven by VEGF family members, can occur directly or indirectly through macrophage recruitment. Corneal injuries and diseases disrupt these privileges, reducing graft survival rates following transplantation. However, modulation of lymphangiogenesis offers potential interventions to promote graft survival and expedite corneal edema resolution.This review underscores the intricate interplay between lymphatic vessels, immune privilege, and corneal pathologies, highlighting innovative therapeutic possibilities. Future investigations should explore the modulation of lymphangiogenesis to enhance corneal health and transparency, as well as corneal graft survival, and this benefits patients with various corneal conditions.

Current Advances in Corneal Stromal Stem Cell Biology and Therapeutic Applications.

Corneal stromal stem cells (CSSCs) are of particular interest in regenerative ophthalmology, offering a new therapeutic target for corneal injuries and diseases. This review provides a comprehensive examination of CSSCs, exploring their anatomy, functions, and role in maintaining corneal integrity. Molecular markers, wound healing mechanisms, and potential therapeutic applications are discussed. Global corneal blindness, especially in more resource-limited regions, underscores the need for innovative solutions. Challenges posed by corneal defects, emphasizing the urgent need for advanced therapeutic interventions, are discussed. The review places a spotlight on exosome therapy as a potential therapy. CSSC-derived exosomes exhibit significant potential for modulating inflammation, promoting tissue repair, and addressing corneal transparency. Additionally, the rejuvenation potential of CSSCs through epigenetic reprogramming adds to the evolving regenerative landscape. The imperative for clinical trials and human studies to seamlessly integrate these strategies into practice is emphasized. This points towards a future where CSSC-based therapies, particularly leveraging exosomes, play a central role in diversifying ophthalmic regenerative medicine.

Combined Osteopontin Blockade and Type 2 Classical Dendritic Cell Vaccination as Effective Synergetic Therapy for Conjunctival Melanoma.

Angiogenesis and immune protection are essential at the onset of tumorigenesis. Angiogenesis serves to nourish the tumor, and prevention of immune defenses, for example, by dendritic cells (DCs), allows tumor growth. In this study, we investigated whether there are factors with dual functions that are both angiogenic and immunomodulatory and represent a therapeutic target. We analyzed 1) innate immune responses intratumorally and in draining lymph nodes and 2) angiogenic factors in conjunctival melanoma (CM), a potentially lethal malignant tumor at the ocular surface whose immune and vascular responses are largely unknown. For this purpose, an HGF-Cdk4R24C model in immunocompetent C57BL/6 mice was used and revealed that CD103- type 2 classical DC (cDC2s) were the most abundant DC subtype in healthy conjunctiva, whereas in CM, CD103- cDC2s, CD103+ type 1 cDCs, monocyte-derived DCs, and plasmacytoid DCs were significantly increased. In our analysis of angiogenic factors in CM, the examination of 53 angiogenesis-related factors that might interact with DCs identified osteopontin (OPN) as a major tumor-derived protein that interacts with DCs. Consistent with these findings, 3) a dual therapeutic strategy that inhibited tumor cell function by an OPN blocking Ab while enhancing the immune response by cDC2 vaccination resulted in 35% failure of tumor development. Moreover, tumor progression, monocyte-derived DC infiltration, and intratumoral angiogenesis were significantly reduced, whereas survival and CD8+ T cell infiltration were increased in treated mice compared with the control group. Therefore, we identified OPN blockade in combination with cDC2 vaccination as a potential future therapeutic intervention for early stages of CM by combining antiangiogenic and host immune stimulating effects.

The unique ORF8 protein from SARS-CoV-2 binds to human dendritic cells and induces a hyper-inflammatory cytokine storm.

The novel coronavirus pandemic, first reported in December 2019, was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection leads to a strong immune response and activation of antigen-presenting cells, which can elicit acute respiratory distress syndrome (ARDS) characterized by the rapid onset of widespread inflammation, the so-called cytokine storm. In response to viral infections, monocytes are recruited into the lung and subsequently differentiate into dendritic cells (DCs). DCs are critical players in the development of the acute lung inflammation that causes ARDS. Here we focus on the interaction of a specific SARS-CoV-2 open reading frame protein, ORF8, with DCs. We show that ORF8 binds to DCs, causes a pre-maturation of differentiating DCs, and induces the secretion of multiple proinflammatory cytokines by these cells. In addition, we identified DC-SIGN as a possible interaction partner of ORF8 on DCs. Blockade of ORF8 leads to reduced production of IL-1ß, IL-6, IL-12p70, TNF-α, MCP-1 (also named CCL2), and IL-10 by DCs. Therefore, a neutralizing antibody blocking the ORF8-mediated cytokine and chemokine response could be an improved therapeutical strategy against severe SARS-CoV-2.

Immediate postoperative topical lidocaine gel for the treatment of eye pain following corneal abrasion in descemet membrane endothelial keratoplasty (DMEK) under general anaesthesia: a pilot retrospective analysis.

BACKGROUND: Patients undergoing corneal abrasion as part of Descemet membrane endothelial keratoplasty (DMEK) under general anesthesia suffer from early burning pain postoperatively. This pain appears to be poorly treatable with systemic analgesics. This study aims to evaluate postoperative pain management using topical lidocaine gel after DMEK with iatrogenic corneal abrasion. METHODS: Retrospective analysis of 28 consecutive patients undergoing DMEK with corneal abrasion from October 19, 2021, to November 12, 2021, at a German university hospital. Patients during week 1 and 2 received peri-operative standard pain treatment (cohort S) and additional local lidocaine gel during week 3 and 4 immediately postoperatively (cohort L). RESULTS: 13 patients were included in cohort S and 15 patients in cohort L. At awakening all patients (100%) in cohort S reported burning pain, and six of 15 patients (40%) in cohort L reported burning pain. Burning pain scores were significantly lower in cohort L (p < 0.001 at awakening, p < 0.001 at 10 min, p < 0.001 at 20 min, p < 0.001 at 30 min, p = 0.007 at 40 min after awakening, and p < 0.001 at leaving recovery room). No significant differences between cohort S and cohort L were detected concerning surgical outcome during 1-month-follow-up (p = 0.901 for best corrected visual acuity). CONCLUSION: Patients undergoing DMEK with corneal abrasion suffer significant pain in the recovery room. A single dose of topic lidocaine gel reduces the early postoperative burning pain sufficiently and does not affect the surgical outcome.

P49-A103†Allogeneic limbo-DALK: a novel surgical technique for patients with corneal stromal disease and limbal stem cell deficiency.

PURPOSE: To describe a novel corneal surgical technique combining Deep Anterior Lamellar Keratoplasty (DALK) with grafting of allogeneic limbal stem cells (limbo-DALK) as treatment for eyes with corneal stromal pathology and limbal stem cell deficiency (LSCD). METHODS: This is a series of six Limbo-DALKs in five eyes of five patients. One patient received a second limbo-DALK after graft failure following the first procedure. Two of the donor corneae were HLA matched. Clinical records of included patients were reviewed retrospectively. All patients had been diagnosed with LSCD due to various pathologies. Analysed data included demographic data, diagnoses and clinical history, graft visualization and thickness measurements by anterior segment OCT, visual acuity and epithelial status. Follow-up visits were 6 weeks and 3, 6, 9, 12 and 18 months postoperatively with final suture removal at 18 months and further follow-up examinations twice yearly thereafter. RESULTS: Two grafts showed total epithelial closure after 2 days, two after 14 days. In one eye, full closure of corneal epithelium did not occur after the first limbo-DALK, but could be achieved one month after second limbo-DALK. No endothelial graft rejection was seen. CONCLUSION: Based on data from this pilot series, limbo-DALK seems to be a novel viable surgical approach for eyes with severe LSCD and stromal corneal pathology.

P35-A133†Novel eccentric corneoscleral donor preparation technique providing corneoscleral tectonic and central split corneal grafts for multiple recipients.

Today, split cornea technique is an established procedure and is mostly used for two recipients by combining deep anterior lamellar keratoplasty (DALK) and Descemet membrane endothelial keratoplasty (DMEK) surgeries. However, for some surgical interventions including block excision with tectonic corneoscleral grafting, split cornea procedure is not planned regularly up to now. In the run-up for this procedure, normally a donor cornea with a bigger scleral ring is gained. Nonetheless, the preparation of the tectonic graft for covering the corneoscleral defect after block excision results in a rest donor cornea transplant which is normally too small for further regular size penetrating keratoplasties (PKs) or combined DALK/DMEK surgeries. However, using a modified donor transplant trephination technique, a corneoscleral transplant for regular size keratoplasties can be gained, also after preparation of a tectonic graft for block excision. Herein, we describe shortly this novel donor preparation technique, the differences compared to the standard procedure, possible applications, and the advantages and disadvantages for the first time.

ABCB5+ Limbal Epithelial Stem Cells Inhibit Developmental but Promote Inflammatory (Lymph) Angiogenesis While Preventing Corneal Inflammation.

The limbus, the vascularized junction between the cornea and conjunctiva, is thought to function as a barrier against corneal neovascularization. However, the exact mechanisms regulating this remain unknown. In this study, the limbal epithelial stem cell (LESC) marker ABCB5 was used to investigate the role of LESCs in corneal neovascularization. In an ABCB5KO model, a mild but significant increase of limbal lymphatic and blood vascular network complexity was observed in developing mice (4 weeks) but not in adult mice. Conversely, when using a cornea suture model, the WT animals exhibited a mild but significant increase in the number of lymphatic vessel sprouts compared to the ABCB5KO, suggesting a contextual anti-lymphangiogenic effect of ABCB5 on the limbal vasculature during development, but a pro-lymphangiogenic effect under inflammatory challenge in adulthood. In addition, conditioned media from ABCB5-positive cultured human limbal epithelial cells (ABCB5+) stimulated human blood and lymphatic endothelial cell proliferation and migration. Finally, a proteomic analysis demonstrated ABCB5+ cells have a pro(lymph)angiogenic as well as an anti-inflammatory profile. These data suggest a novel dual, context-dependent role of ABCB5+ LESCs, inhibiting developmental but promoting inflammatory (lymph)angiogenesis in adulthood and exerting anti-inflammatory effects. These findings are of high clinical relevance in relation to LESC therapy against blindness.

Corneal Hydrops - Aetiology and Advanced Therapeutic Strategies. / Der korneale Hydrops ­ Ursachen und moderne Therapieansätze.

Acute hydrops refers to sudden corneal edema caused by rupture of Descemet's membrane (DM) - often in progressive keratectasia. It leads to a sudden decrease in visual acuity, pain, and foreign body sensation as well as an increased glare sensation. Acute hydrops usually heals with scarring within months, but complications such as corneal perforation, infectious keratitis, and corneal vascularization may occur. The prevalence in keratoconus patients is 2.6 to 2.8%. Risk factors include keratoconjunctivitis vernalis, atopic dermatitis, high keratometry, male gender, and eye rubbing. Keratoplasty should be avoided in the acute phase. The prognosis of the graft is reduced, and after scar healing of the hydrops, wearing contact lenses or glasses may be possible again. Conservative therapy alone with lubricants and hyperosmolar eye drops, prophylactic antibiotic eye drops to prevent superinfection, and topical steroids was long considered the only possible form of treatment. However, healing under conservative therapy takes an average of over 100 days. In the meantime, there are different surgical strategies that rapidly shorten the healing and thus the recovery phase of the patients to a few days. If the DM is detached without tension, a simple injection of gas into the anterior chamber can already lead to reattachment and thus to almost immediate deswelling of the cornea. If the DM is under tension, predescemetal sutures combined with a gas injection into the anterior chamber can flatten the cornea and reattach the DM. Mini-Descemet membrane endothelial keratoplasty (mini-DMEK) allows for sutureless closure of the DM defect by transplantation of a small (< 5 mm) graft. In cases of particularly large DM tears and very pronounced hydrops, suture loosening and relapse may occur after the placement of predescemetal sutures. Mini-DMEK can then lead to permanent healing, but in contrast to simple corneal sutures, it is usually performed under general anesthesia and by aid of intraoperative optical coherence tomography. The very good results with regard to the rapid healing prove that surgical therapy makes sense in the vast majority of patients with acute hydrops and should be initiated quickly.

Future directions in managing aniridia-associated keratopathy.

Congenital aniridia is a panocular disorder that is typically characterized by iris hypoplasia and aniridia-associated keratopathy (AAK). AAK results in the progressive loss of corneal transparency and thereby loss of vision. Currently, there is no approved therapy to delay or prevent its progression, and clinical management is challenging because of phenotypic variability and high risk of complications after interventions; however, new insights into the molecular pathogenesis of AAK may help improve its management. Here, we review the current understanding about the pathogenesis and management of AAK. We highlight the biological mechanisms involved in AAK development with the aim to develop future treatment options, including surgical, pharmacological, cell therapies, and gene therapies.