Keratoconus International Consortium (KIC)- advancing keratoconus research.

CLINICAL RELEVANCE: The Keratoconus International Consortium (KIC) will allow better understanding of keratoconus. BACKGROUND: Keratoconus is a disorder characterised by corneal elevation and thinning, leading to reduced vision. The current gaps in understanding of this disease will be discussed and the need for a multi-pronged and multi-centre engagement to enhance our understanding of keratoconus will be highlighted. DESIGN: KIC has been established to address the gaps in our understanding of keratoconus with the aim of collecting baseline as well as longitudinal data on several fields. PARTICIPANTS: Keratoconus and control (no corneal condition) subjects from different sites globally will be recruited in the study. METHODS: KIC collects data using an online, secure database, which enables standardised data collection at member sites. Data fields collected include medical history, clinical features, quality of life and economic burden questionnaires and possible genetic sample collection from patients of different ethnicities across different geographical locations. RESULTS: There are currently 40 Australian and international clinics or hospital departments who have joined the KIC. Baseline data has so far been collected on 1130 keratoconus patients and indicates a median age of 29.70 years with 61% being male. A total of 15.3% report a positive family history of keratoconus and 57.7% self-report a history of frequent eye rubbing. CONCLUSION: The strength of this consortium is its international, collaborative design and use of a common data collection tool. Inclusion and analyses of cross-sectional and longitudinal data will help answer many questions that remain in keratoconus, including factors affecting progression and treatment outcomes.

The association between keratoconus and allergic eye diseases: A systematic review and meta-analysis.

BACKGROUND: To investigate the association between keratoconus (KC) and allergic eye diseases, eye rubbing, and atopy. METHODS: PubMed, Web of Science, Scopus, and Cochrane databases were searched for studies investigating eye allergy, atopy, and eye rubbing as risk factors for KC up to April 2021. Two authors independently screened all titles and abstracts against the predefined inclusion and exclusion criteria. The study analysed the prevalence of KC and its risk factors, including eye rubbing, family history of KC, atopy, and allergic eye diseases. The National Institutes of Health Study Quality Assessment Tool was used. Pooled data are presented as odds ratios (OR) and 95% confidence intervals (CI). The analysis was conducted using RevMan version 5.4 software. RESULTS: The initial search yielded 573 articles. After screening, 21 studies were identified for qualitative analysis and 15 for quantitative synthesis. A significant association was found between KC and eye rubbing (OR = 5.22, 95% CI [2.80, 9.75], p < 0.00001), family history of KC (OR = 6.67, 95% CI [4.77, 9.33], p < 0.00001), and allergies (OR = 2.21, 95% CI [1.57, 3.13], p < 0.00001). However, no significant association was found between KC and allergic eye disease (OR = 1.82, 95% CI [0.37, 8.97], p = 0.46), atopy (OR = 1.54, 95% CI [0.58, 4.09], p = 0.39), allergic rhinitis (OR = 0.85, 95% CI [0.54, 1.33], p = 0.47), smoking (OR = 0.96, 95% CI [0.76, 1.21], p = 0.73), and asthma (OR = 1.58, 95% CI [0.99, 2.53], p = 0.05). CONCLUSION: Significant associations were observed between KC and eye rubbing, family history, and allergy, but not with allergic eye disease, atopy, asthma, and allergic rhinitis.

Comparison of penetrating and endothelial keratoplasty in patients with iridocorneal endothelial syndrome: A registry study.

BACKGROUND: To compare graft survival of endothelial keratoplasty (EK) versus penetrating keratoplasty (PK) in patients with iridocorneal endothelial (ICE) syndrome and identify ocular features associated with graft survival. METHODS: Observational, prospective, cohort study. A total of 30 806 first grafts performed between 1985 and 2020 were identified through the Australian Corneal Graft Registry and included in this observational, prospective cohort study. A total of 196 eyes underwent a primary corneal graft for ICE syndrome. Kaplan-Meier graft survival plots and Chi-squared tests were performed to identify graft survival rates for EK and PK. A history of raised intraocular pressure (IOP) was also recorded and analysed. Graft survival of eyes with ICE syndrome were compared to that of other indications. RESULTS: Grafts performed for ICE syndrome increased to 0.8% of all cases during the 2005 to 2020 period compared with 0.5% between 1985 to 2004 (χ2 =9.35, p = 0.002). From 2010, EK surpassed PK as the preferred graft type. Survival of primary grafts in eyes with ICE syndrome was lower than for other indications (log-rank = 56.62, p < 0.001). Graft survival was higher following PK than Descemet stripping (automated) endothelial keratoplasty (DS(A)EK) (log-rank = 10.56, p = 0.001). Graft survival was higher in eyes without a history of raised IOP compared to those with a reported history of raised IOP (log-rank = 13.06, p < 0.001). CONCLUSIONS: ICE syndrome carries a poor prognosis for graft survival. DS(A)EK had a poorer prognosis than PK. A history of raised IOP is associated with higher risk of graft failure.

The association between keratoconus and allergic eye diseases: A systematic review and meta-analysis.

BACKGROUND: To investigate association between keratoconus and allergic eye diseases, eye rubbing, and atopy. METHODS: PubMed, Web of Science, Scopus, and Cochrane were searched for relevant published studies from inception to April 2021 without restrictions or filters. We included case-control, cohort, and cross-sectional studies that investigated eye allergy, atopy, or eye rubbing as possible risk factors for KC. Two authors independently screened all titles and abstracts against predefined inclusion and exclusion criteria. This study analysed keratoconus prevalence and risk factors including eye rubbing, family history of keratoconus, atopy, and allergic eye diseases. The National Institute of Health Study Quality Assessment tool was utilised. Pooled data were presented as odds ratio (OR) and 95% confidence intervals (CI). Analysis was conducted using RevMan version 5.3 software. RESULTS: Out of 573 articles, we excluded 161 duplicates than 361 articles by title and abstract screening. The remaining 51 articles underwent full-text screening, and 29 articles were excluded. Twenty-one studies were included in the qualitative synthesis and fifteen for quantitative synthesis. There was no significant association found between KC and allergic eye diseases (OR = 1.03, 95% CI [0.96, 1.11], p = 0.45), eye rubbing (OR = 1.59, 95% CI [0.70, 3.63], p = 0.27), or atopy (OR = 1.08, 95% CI [0.80, 1.44], p = 0.62). CONCLUSION: No significant association was observed between KC and allergic eye disease, eye rubbing, or atopy. Further prospective studies are needed to clarify and validate these findings.

Eye rubbing in the aetiology of keratoconus: a systematic review and meta-analysis.

PURPOSE: Keratoconus is a potentially blinding condition that slowly deforms the cornea in young people. Despite the increasing prevalence of keratoconus, the exact aetiology of the condition is unknown. This first systematic review examines the evidence of eye rubbing and its association with keratoconus and presents the findings of the meta-analysis. METHODS: Two independent reviewers searched the electronic databases for all potential articles published from 1st of January 1900 to 31st of July 2020 on eye rubbing and keratoconus. The researchers assessed the methodological quality of the studies using the Newcastle-Ottawa scale for observational studies. The assessment for statistical heterogeneity was estimated using chi-square and I-square (I2) tests. A p value of < 0.05 was considered as statistically significant and I2 < 30% as homogenous. Begg funnel plot was used to interpret the asymmetry or small study effects. RESULTS: Eight case-control studies were included in this systematic review. Two studies assessed eye rubbing without odds ratios and thus were excluded. The pooled odds ratios for the six remaining studies included in the meta-analysis was 6.46 (95% CI 4.12-10.1). The study results were heterogenous (I2 = 71.69 [95% CI 35.14-87.88]). All the studies scored moderate quality methodology on the Newcastle-Ottawa scale. Begg funnel plot showed asymmetry supporting heterogeneity. CONCLUSION: Eye rubbing showed consistent association with keratoconus. However, the current evidence is limited to only a small number of case-control studies which present as heterogeneous and of sub-optimal methodological quality. Additionally, the cause-effect temporal relationship cannot be determined. Further studies are needed to address this intricate relationship of eye rubbing and its induction, ongoing progression, and severity of keratoconus.

Risk factors and association with severity of keratoconus: the Australian study of Keratoconus.

SIGNIFICANCE: Our results show that asthmatic patients tend to have more severe KC and thus close monitoring for disease progression would be advised, and appropriate treatment strategies may be actioned stabilise the condition that may reduce the need for future corneal transplantation. PURPOSE: To explore a wide range of risk factors associated with the severity of keratoconus (KC). METHODS: A cross-sectional study of KC patients was undertaken in Melbourne, Australia. A questionnaire addressing age, gender, educational background, ocular and medical history, smoking and alcohol consumption, and physical examination comprising anthropometric measurements was collected; eye examination was undertaken. The associations between a range of risk factors and the severity of KC were determined using univariate and multivariable linear regression analyses. RESULTS: A total of 260 KC subjects were included in this study. Mean age of subject was 35.5 (SD = 14.8) years and the majority of the subjects were European 171 (68.2%). Initial univariate regression analysis identified the following risk factors at the p < 0.1 level with KC: higher body mass index, smoking cigarettes, diabetes, rheumatoid arthritis and asthma were associated with increased severity of KC, whereas eczema was associated with less severe KC. Following multivariable regression analysis, only asthma remained as a significant risk factor associated with 2.2 diopters (D) steeper average mean keratometry compared to KC subjects having no asthma [p = 0.03; ß = 2.18; 95% confidence intervals: 1.22, 4.14]. CONCLUSION: Our study describes the comprehensive assessment of all the known risk factors in a large KC cohort recruited in Australia. Our study has reported asthma as the only risk factor found to be significantly associated with the severity of KC. The results of this study allow us to better understand the aetiology of KC and such knowledge could be useful in instigate systemic management of patients to slow or prevent KC.

Economic impact of keratoconus using a health expenditure questionnaire: A patient perspective.

IMPORTANCE: This is the first study to estimate the lifetime costs associated with keratoconus based on a questionnaire completed by patients and highlights the significant economic burden of the disease. As keratoconus affects individuals from a young age, the study highlights keratoconus as a public health concern. BACKGROUND: Keratoconus is a disorder characterized by corneal steepening and thinning, leading to reduced visual acuity. To date, there have been no studies evaluating the economic costs of keratoconus from a patient's perspective. DESIGN: A randomized cross-sectional study undertaken in Australia where keratoconus subjects were recruited from public and private ophthalmology and optometry clinics. PARTICIPANTS: A total of 100 participants completed the questionnaire: median age was 31 years and 57% were males. METHODS: A keratoconus health expenditure questionnaire was designed to assess direct and indirect expenditures for each individual. MAIN OUTCOME MEASURES: Total direct and indirect costs associated with the condition were calculated along with the estimated lifetime per capita costs. RESULTS: The total cost related to direct and indirect care was estimated to be AUD 3365. By applying our cost data to keratoconus prevalence data for the Australian population, the total cost is estimated to be approximately AUD 44.7 million per year in Australia. CONCLUSIONS AND RELEVANCE: Our results show that the costs associated with the diagnosis and management of keratoconus represent a significant cost to patients. An understanding of this is important not only to individuals and their families, but also health care providers, health insurers and the wider health system.

Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy.

BACKGROUND: Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are sight-threatening complications of diabetes mellitus and leading causes of adult-onset blindness worldwide. Genetic risk factors for diabetic retinopathy (DR) have been described previously, but have been difficult to replicate between studies, which have often used composite phenotypes and been conducted in different populations. This study aims to identify genetic risk factors for DME and PDR as separate complications in Australians of European descent with type 2 diabetes. METHODS: Caucasian Australians with type 2 diabetes were evaluated in a genome-wide association study (GWAS) to compare 270 DME cases and 176 PDR cases with 435 non-retinopathy controls. All participants were genotyped by SNP array and after data cleaning, cases were compared to controls using logistic regression adjusting for relevant covariates. RESULTS: The top ranked SNP for DME was rs1990145 (p = 4.10 × 10- 6, OR = 2.02 95%CI [1.50, 2.72]) on chromosome 2. The top-ranked SNP for PDR was rs918519 (p = 3.87 × 10- 6, OR = 0.35 95%CI [0.22, 0.54]) on chromosome 5. A trend towards association was also detected at two SNPs reported in the only other reported GWAS of DR in Caucasians; rs12267418 near MALRD1 (p = 0.008) in the DME cohort and rs16999051 in the diabetes gene PCSK2 (p = 0.007) in the PDR cohort. CONCLUSION: This study has identified loci of interest for DME and PDR, two common ocular complications of diabetes. These findings require replication in other Caucasian cohorts with type 2 diabetes and larger cohorts will be required to identify genetic loci with statistical confidence. There is considerable overlap in the patient cohorts with each retinopathy subtype, complicating the search for genes that contribute to PDR and DME biology.

Nature and incidence of severe limbal stem cell deficiency in Australia and New Zealand.

BACKGROUND: This study aimed to determine the nature and incidence of severe limbal stem cell deficiency (LSCD) in Australia and New Zealand. DESIGN: A 1-year pilot surveillance study with a 1-year follow-up period was conducted in association with the Australian and New Zealand Ophthalmic Surveillance Unit. PARTICIPANTS: The study included patients reported by practising ophthalmologists on the Surveillance Unit's database. METHODS: Ophthalmologists were provided with a definition of severe limbal stem cell deficiency, contacted on a monthly basis by the Unit and asked to report newly diagnosed cases. MAIN OUTCOME MEASURES: Severe LSCD was defined as at least 6 clock hours of whorl-like epitheliopathy, an opaque epithelium arising from the limbus, late fluorescein staining of the involved epithelium and superficial corneal neovascularization or conjunctivalization. RESULTS: On average, 286 report cards were sent by the Surveillance Unit to practising ophthalmologists each month (total 3429 over 12 months) and the Unit received an average of 176 responses per month (total 2111; 62% response rate). During the 1-year study period from April 2013 to March 2014, 14 positive cases were reported to the Unit. A range of underlying aetiologies were implicated, with contact lens over-wear and cicatrizing conjunctivitis being the most common (n = 3). CONCLUSIONS: This surveillance study is the first worldwide to document the incidence of limbal stem cell deficiency; however, because of study design limitations, it is likely to have been under-reported. It provides novel data on the demographics, clinical conditions and management of patients with limbal stem cell deficiency as reported by treating ophthalmologists.

Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene.

AIMS/HYPOTHESIS: Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study. METHODS: Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot. RESULTS: The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina. CONCLUSIONS/INTERPRETATION: Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.

Common Sequence Variation in the VEGFC Gene Is Associated with Diabetic Retinopathy and Diabetic Macular Edema.

PURPOSE: To investigate associations between single nucleotide polymorphisms (SNPs) in the VEGFC gene and the development of diabetic retinopathy (DR) in white patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). DESIGN: Cross-sectional, case control study. PARTICIPANTS: White patients with T1DM or T2DM (n = 2899) were recruited from ophthalmology and endocrine clinics in Australia and the United Kingdom. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be receiving oral hypoglycemic treatment or insulin. METHODS: Participants were categorized according to their worst-ever DR grading, as having "no DR" (no history of nonproliferative DR [NPDR], proliferative DR [PDR], or diabetic macular edema [DME]) or "any DR" (further subclassified as NPDR or PDR, without or with DME). Clinical characteristics, glycemic control (hemoglobin A1c [HbA1c]), and presence of diabetic complications were determined at recruitment. Genotyping was performed for 13 VEGFC tag SNPs. MAIN OUTCOME MEASURES: Odds ratios (ORs) were determined for associations with DR of VEGFC tag SNPs, individually and within haplotypes. Logistic regression was used to adjust for clinical covariates, including DM type, age, sex, DM duration, hypertension, nephropathy, HbA1c, and smoking. RESULTS: Participants with DM but "no DR" (n = 980) were compared with 1919 participants with DM and "any DR." Three VEGFC SNPs were associated with DR after logistic regression: rs17697419 (P = 0.001; OR, 0.67; confidence interval [CI], 0.52-0.85), rs17697515 (P = 0.001; OR, 0.62; CI, 0.47-0.81), and rs2333526 (P = 0.005; OR, 0.69; CI, 0.54-0.90). rs17697515 Was also specifically associated with DME in those with T2DM (P = 0.004; OR, 0.53; CI, 0.35-0.82). Haplotype analysis revealed 2 significantly associated haplotypes, both protective against DR development. CONCLUSIONS: Significant associations were found between VEGFC tag SNPs (individually and within haplotypes) and the presence of any DR or DME in white participants with T1DM and T2DM.

Activation of the lectin pathway of complement in experimental human keratitis with Pseudomonas aeruginosa.

PURPOSE: Pseudomonas aeruginosa (P. aeruginosa) microbial keratitis (MK) is a sight-threatening disease. Previous animal studies have identified an important contribution of the complement system to the clearance of P. aeruginosa infection of the cornea. Mannose-binding lectin (MBL), a pattern recognition receptor of the lectin pathway of complement, has been implicated in the host defense against P. aeruginosa. However, studies addressing the role of the lectin pathway in P. aeruginosa MK are lacking. Hence, we sought to determine the activity of the lectin pathway in human MK caused by P. aeruginosa. METHODS: Primary human corneal epithelial cells (HCECs) from cadaveric donors were exposed to two different P. aeruginosa strains. Gene expression of interleukin (IL)-6, IL-8, MBL, and other complement proteins was determined by reverse transcription-polymerase chain reaction (RT-PCR) and MBL synthesis by enzyme-linked immunosorbent assay and intracellular flow cytometry. RESULTS: MBL gene expression was not detected in unchallenged HCECs. Exposure of HCECs to P. aeruginosa resulted in rapid induction of the transcriptional expression of MBL, IL-6, and IL-8. In addition, expression of several complement proteins of the classical and lectin pathways, but not the alternative pathway, were upregulated after 5 h of challenge, including MBL-associated serine protease 1. However, MBL protein secretion was not detectable 18 h after challenge with P. aeruginosa. CONCLUSIONS: MK due to P. aeruginosa triggers activation of MBL and the lectin pathway of complement. However, the physiologic relevance of this finding is unclear, as corresponding MBL oligomer production was not observed.

Genetic study of diabetic retinopathy: recruitment methodology and analysis of baseline characteristics.

BACKGROUND: Diabetic retinopathy (DR) is a blinding disease of increasing prevalence that is caused by a complex interplay of genetic and environmental factors. Here we describe the patient recruitment methodology, case and control definitions, and clinical characteristics of a study sample to be used for genome-wide association analysis to detect genetic risk variants of DR. METHODS: One thousand six hundred sixty-nine participants with either type 1 (T1) or type 2 (T2) diabetes mellitus (DM) aged 18 to 95 years were recruited in Australian hospital clinics. Individuals with T2DM had disease duration of at least 5 years and were taking oral hypoglycaemic medication, and/or insulin therapy. Participants underwent ophthalmic examination. Medical history and biochemistry results were collected. Venous blood was obtained for genetic analysis. RESULTS: Six hundred eighty-three diabetic cases (178 T1DM and 505 T2DM participants) with sight-threatening DR, defined as severe non-proliferative DR, proliferative DR or diabetic macular oedema were included in this analysis. Eight hundred twelve individuals with DM but no DR or minimal non-proliferative DR were recruited as controls (191 with T1DM and 621 with T2DM). The presence of sight-threatening DR was significantly correlated with DM duration, hypertension, nephropathy, neuropathy, HbA1C and body mass index. Diabetic macular oedema was associated with T2DM (P < 0.001), whereas proliferative DR was associated with T1DM (P < 0.001). CONCLUSIONS: Adoption of a case-control study design involving extremes of the DR phenotype makes this a suitable cohort, for a well-powered genome-wide association study to detect genetic risk variants for DR.

Australian Nurse Engagement in Eye Care: A National Survey.

Purpose: An estimated 13 million Australians live with one or more chronic eye conditions, with prevalence increasing. Eye care services today and in the future rely on effective workforces, in which nurses play a pivotal role. Despite nurse involvement in eye care, there is no information describing their engagement, deployment, training, and opinion. This paper offers the first review of nurse engagement in eye care in Australia. Methods: We conducted an e-survey on Australian nurse engagement in eye care. Quantitative questions were analysed by descriptive, chi-square and bivariate correlation coefficients with assumed power of 0.80, and significance of p=0.05. Grounded theory, sentiment and saturation analysis extracted key themes, meaning and opinion from the qualitative questions. Results: There were n=238 Australian nurse participants. Results indicated they were satisfied with their role, engaged in a wide range of healthcare and eye care setting and organisations, and adapted to their employer. Task-shifting "to" and "from" nurses was not universally supported but recognised by participants as necessary. Of concern, the results suggested that 68.6% of our participants would exit eye care over the next ten years, with insufficient entry pathways into the field for graduate and early-career nurses. Conclusion: For Australia to meet and sustain eye care services for its population, steps must be taken to improve exposure and entry to the field for students, graduates, and early-career nurses. Strategies to train and prepare nurses for task-shifting are urgently required and the eye care nursing sector must professionalise to achieve positive change.

Single nuclei transcriptomics of the in situ human limbal stem cell niche.

The corneal epithelium acts as a barrier to pathogens entering the eye; corneal epithelial cells are continuously renewed by uni-potent, quiescent limbal stem cells (LSCs) located at the limbus, where the cornea transitions to conjunctiva. There has yet to be a consensus on LSC markers and their transcriptome profile is not fully understood, which may be due to using cadaveric tissue without an intact stem cell niche for transcriptomics. In this study, we addressed this problem by using single nuclei RNA sequencing (snRNAseq) on healthy human limbal tissue that was immediately snap-frozen after excision from patients undergoing cataract surgery. We identified the quiescent LSCs as a sub-population of corneal epithelial cells with a low level of total transcript counts. Moreover, TP63, KRT15, CXCL14, and ITGß4 were found to be highly expressed in LSCs and transiently amplifying cells (TACs), which constitute the corneal epithelial progenitor populations at the limbus. The surface markers SLC6A6 and ITGß4 could be used to enrich human corneal epithelial cell progenitors, which were also found to specifically express the putative limbal progenitor cell markers MMP10 and AC093496.1.

Exploring single-cell RNA sequencing as a decision-making tool in the clinical management of Fuchs' endothelial corneal dystrophy.

Single-cell RNA sequencing (scRNA-seq) has enabled the identification of novel gene signatures and cell heterogeneity in numerous tissues and diseases. Here we review the use of this technology for Fuchs' Endothelial Corneal Dystrophy (FECD). FECD is the most common indication for corneal endothelial transplantation worldwide. FECD is challenging to manage because it is genetically heterogenous, can be autosomal dominant or sporadic, and progress at different rates. Single-cell RNA sequencing has enabled the discovery of several FECD subtypes, each with associated gene signatures, and cell heterogeneity. Current FECD treatments are mainly surgical, with various Rho kinase (ROCK) inhibitors used to promote endothelial cell metabolism and proliferation following surgery. A range of emerging therapies for FECD including cell therapies, gene therapies, tissue engineered scaffolds, and pharmaceuticals are in preclinical and clinical trials. Unlike conventional disease management methods based on clinical presentations and family history, targeting FECD using scRNA-seq based precision-medicine has the potential to pinpoint the disease subtypes, mechanisms, stages, severities, and help clinicians in making the best decision for surgeries and the applications of therapeutics. In this review, we first discuss the feasibility and potential of using scRNA-seq in clinical diagnostics for FECD, highlight advances from the latest clinical treatments and emerging therapies for FECD, integrate scRNA-seq results and clinical notes from our FECD patients and discuss the potential of applying alternative therapies to manage these cases clinically.