{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:12Z","timestamp":1787027832888,"version":"build-2736575974"},"reference-count":71,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["RF-2016-02361159"],"award-info":[{"award-number":["RF-2016-02361159"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) syndrome is caused by heterozygous missense point mutations in the p63 gene, an important transcription factor during embryogenesis and for stem cell differentiation in stratified epithelia. Most of the cases are sporadic, related to de novo mutations arising during early-stage development. Familial cases show an autosomic dominant inheritance. The major cause of visual morbidity is limbal stem cell failure, which develops in the second to third decade of life. Patients often show ocular surface alterations, such as recurrent blepharitis and conjunctivitis, superficial microlesions of the cornea, and spontaneous corneal perforation and ulceration, leading to progressive corneal clouding and eventually visual loss. No definitive cures are currently available, and treatments to alleviate symptoms are only palliative. In this review, we will discuss the proposed therapeutic strategies that have been tested or are under development for the management of the ocular defects in patients affected by EEC syndrome: (i) gene therapy-based approaches by means of Allele-Specific (AS) siRNAs to correct the p63 mutations; (ii) cell therapy-based approaches to replenish the pool of limbal stem cells; and (iii) drug therapy to correct\/bypass the genetic defect. However, as the number of patients with EEC syndrome is too limited, further studies are still necessary to prove the effectiveness (and safety) of these innovative therapeutic approaches to counteract the premature differentiation of limbal stem cells.<\/jats:p>","DOI":"10.3390\/cells12030495","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T03:04:23Z","timestamp":1675393463000},"page":"495","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Innovative Therapeutic Approaches for the Treatment of the Ocular Morbidities in Patients with EEC Syndrome"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8760-2343","authenticated-orcid":false,"given":"Vanessa","family":"Barbaro","sequence":"first","affiliation":[{"name":"Fondazione Banca degli Occhi del Veneto Onlus, Via Paccagnella, 11, 30174 Venice, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2078-6189","authenticated-orcid":false,"given":"Filippo","family":"Bonelli","sequence":"additional","affiliation":[{"name":"Fondazione Banca degli Occhi del Veneto Onlus, Via Paccagnella, 11, 30174 Venice, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3983-3328","authenticated-orcid":false,"given":"Stefano","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Fondazione Banca degli Occhi del Veneto Onlus, Via Paccagnella, 11, 30174 Venice, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"La Vella","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, University Hospital of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enzo","family":"Di Iorio","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, University Hospital of Padua, 35128 Padua, Italy"},{"name":"Department of Molecular Medicine, University of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.ophtha.2011.06.044","article-title":"Limbal stem cell deficiency and ocular phenotype in ectrodactyly-ectodermal dysplasia-clefting syndrome caused by p63 mutations","volume":"119","author":"Kaye","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"262","DOI":"10.4161\/cc.6.3.3796","article-title":"p63-associated disorders","volume":"6","author":"Rinne","year":"2007","journal-title":"Cell Cycle"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1365-2133.2009.09496.x","article-title":"Molecular basis of EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome: Five new mutations in the DNA-binding domain of the TP63 gene and genotype\u2013phenotype correlation","volume":"162","author":"Clements","year":"2010","journal-title":"Br. J. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.bbrc.2022.04.022","article-title":"p63 in corneal and epidermal differentiation","volume":"610","author":"Novelli","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1038\/cdd.2011.81","article-title":"p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53","volume":"18","author":"Melino","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0092-8674(00)81646-3","article-title":"Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome","volume":"99","author":"Celli","year":"1999","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1038\/jid.2010.119","article-title":"p63 in skin development and ectodermal dysplasias","volume":"130","author":"Koster","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1097\/00019605-199604000-00003","article-title":"The EEC syndrome: A literature study","volume":"5","author":"Roelfsema","year":"1996","journal-title":"Clin. Dysmorphol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1086\/323123","article-title":"p63 Gene Mutations in EEC Syndrome, Limb-Mammary Syndrome, and Isolated Split Hand\u2013Split Foot Malformation Suggest a Genotype-Phenotype Correlation","volume":"69","author":"Hamel","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1038\/sj.cdd.4401926","article-title":"Differential roles of p63 isoforms in epidermal development: Selective genetic complementation in p63 null mice","volume":"13","author":"Candi","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.5966\/sctm.2015-0358","article-title":"Personalized Stem Cell Therapy to Correct Corneal Defects Due to a Unique Homozygous-Heterozygous Mosaicism of Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome","volume":"5","author":"Barbaro","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1016\/S0161-6420(85)33847-2","article-title":"Keratopathy in a Family with the Ectrodactyly-Ectodermal Dysplasia-clefting Syndrome","volume":"92","author":"Mawhorter","year":"1985","journal-title":"Ophthalmology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1136\/bjo.73.4.261","article-title":"The EEC syndrome and its ocular manifestations","volume":"73","author":"McNab","year":"1989","journal-title":"Br. J. Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/ajmg.1320370112","article-title":"EEC syndrome: Report on 20 new patients, clinical and genetic considerations","volume":"37","author":"Rodini","year":"1990","journal-title":"Am. J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1136\/jmg.32.9.716","article-title":"Twenty-four cases of the EEC syndrome: Clinical presentation and management","volume":"32","author":"Buss","year":"1995","journal-title":"J. Med. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/eye.1996.73","article-title":"Absent meibomian glands: A marker for EEC syndrome","volume":"10","author":"Bonnar","year":"1996","journal-title":"Eye"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.1097\/IOP.0000000000000060","article-title":"Ectrodactyly Ectodermal Dysplasia Clefting (EEC) syndrome: A rare cause of congenital lacrimal anomalies","volume":"31","author":"Elmann","year":"2015","journal-title":"Ophthalmic Plast. Reconstr. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1111\/j.1399-0004.1972.tb01473.x","article-title":"Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome","volume":"3","author":"Fried","year":"1972","journal-title":"Clin. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/0002-9394(74)90078-6","article-title":"Ocular Manifestations of the Ectrodactyly, Ectodermal Dysplasia, Cleft Lip-Palate Syndrome","volume":"78","author":"Baum","year":"1974","journal-title":"Am. J. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1001\/archopht.1990.01070090041035","article-title":"Results of Penetrating Keratoplasty for the Treatment of Corneal Perforations","volume":"108","author":"Nobe","year":"1990","journal-title":"Arch. Ophthalmol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0002-9394(14)76361-5","article-title":"Penetrating keratoplasty in ectodermal dysplasia","volume":"110","author":"Mader","year":"1990","journal-title":"Am. J. Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1097\/00003226-200305000-00022","article-title":"Penetrating Keratoplasty and Keratolimbal Allograft Transplantation for Corneal Perforations Associated with the Ectodermal Dysplasia Syndrome","volume":"22","author":"Anderson","year":"2003","journal-title":"Cornea"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1046\/j.1525-1470.2003.20203.x","article-title":"The ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC): Report of five cases","volume":"20","author":"Bielsa","year":"2003","journal-title":"Pediatr. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/S0161-6420(00)00475-9","article-title":"Living related conjunctival limbal allograft for the treatment of stem cell deficiency","volume":"108","author":"Daya","year":"2001","journal-title":"Ophthalmology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1056\/NEJMoa0905955","article-title":"Limbal stem-cell therapy and long-term corneal regeneration","volume":"363","author":"Rama","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1016\/j.ophtha.2008.04.039","article-title":"Ex vivo expansion and transplantation of limbal epithelial stem cells","volume":"115","author":"Shortt","year":"2008","journal-title":"Ophthalmology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.ophtha.2004.09.023","article-title":"Outcomes and DNA analysis of ex vivo expanded stem cell allograft for ocular surface reconstruction","volume":"112","author":"Daya","year":"2005","journal-title":"Ophthalmology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1097\/ICO.0000000000001662","article-title":"Cincinnati Protocol for Preoperative Screening and Donor Selection for Ocular Surface Stem Cell Transplantation","volume":"37","author":"Cheung","year":"2018","journal-title":"Cornea"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1097\/ICO.0000000000002729","article-title":"Outcomes of Human Leukocyte Antigen-Matched Allogeneic Cultivated Limbal Epithelial Transplantation in Aniridia-Associated Keratopathy-A Single-Center Retrospective Analysis","volume":"41","author":"Behaegel","year":"2022","journal-title":"Cornea"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.ajo.2006.06.004","article-title":"Ocular surface reconstruction with combination of cultivated autologous oral mucosal epithelial transplantation and penetrating keratoplasty","volume":"142","author":"Inatomi","year":"2006","journal-title":"Am. J. Ophthalmol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1136\/bjo.2003.038497","article-title":"Transplantation of cultivated autologous oral mucosal epithelial cells in patients with severe ocular surface disorders","volume":"88","author":"Nakamura","year":"2004","journal-title":"Br. J. Ophthalmol."},{"key":"ref_32","first-page":"310","article-title":"Woman is first to receive cornea made from \u201creprogrammed\u201d stem cells","volume":"534","author":"Cyranoski","year":"2019","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1089\/cell.2017.0064","article-title":"Oral Mucosa-Derived Induced Pluripotent Stem Cells from Patients with Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome","volume":"20","author":"Trevisan","year":"2018","journal-title":"Cell. Reprogram."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.scr.2018.02.007","article-title":"Generation of a transgene-free human induced pluripotent stem cell line (UNIPDi001-A) from oral mucosa epithelial stem cells","volume":"28","author":"Alvisi","year":"2018","journal-title":"Stem Cell Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.scr.2018.02.008","article-title":"Induced pluripotent stem cells line (UNIPDi003-A) from a patient affected by EEC syndrome carrying the R279H mutation in TP63 gene","volume":"28","author":"Trevisan","year":"2018","journal-title":"Stem Cell Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.scr.2018.02.006","article-title":"Generation of a transgene-free induced pluripotent stem cells line (UNIPDi002-A) from oral mucosa epithelial stem cells carrying the R304Q mutation in TP63 gene","volume":"28","author":"Trevisan","year":"2018","journal-title":"Stem Cell Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1073\/pnas.1201753109","article-title":"Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246\/PRIMA-1MET","volume":"110","author":"Serror","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/nature13426","article-title":"ABCB5 is a limbal stem cell gene required for corneal development and repair","volume":"511","author":"Ksander","year":"2014","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1186\/s13287-021-02272-2","article-title":"Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency","volume":"12","author":"Norrick","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/icb.2012.67","article-title":"Anti-donor immune responses elicited by allogeneic mesenchymal stem cells: What have we learned so far?","volume":"91","author":"Griffin","year":"2013","journal-title":"Immunol. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.trsl.2018.11.003","article-title":"A proof-of-concept clinical trial using mesenchymal stem cells for the treatment of corneal epithelial stem cell deficiency","volume":"206","author":"Calonge","year":"2019","journal-title":"Transl. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1167\/iovs.12-10528","article-title":"Allele-specific siRNA silencing for the common keratin 12 founder mutation in Meesmann epithelial corneal dystrophy","volume":"54","author":"Allen","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1167\/iovs.13-12957","article-title":"siRNA silencing of the mutant keratin 12 allele in corneal limbal epithelial cells grown from patients with Meesmann\u2019s epithelial corneal dystrophy","volume":"55","author":"Courtney","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1167\/iovs.13-13279","article-title":"Development of allele-specific gene-silencing siRNAs for TGFBI Arg124Cys in lattice corneal dystrophy type I","volume":"55","author":"Courtney","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1038\/jid.2011.169","article-title":"Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex","volume":"131","author":"Atkinson","year":"2011","journal-title":"J. Investig. Dermatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1038\/jid.2012.28","article-title":"Generic and personalized RNAi-based therapeutics for a dominant-negative epidermal fragility disorder","volume":"132","author":"Fu","year":"2012","journal-title":"J. Investig. Dermatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1002\/stem.2343","article-title":"Correction of Mutant p63 in EEC Syndrome Using siRNA Mediated Allele-Specific Silencing Restores Defective Stem Cell Function","volume":"34","author":"Barbaro","year":"2016","journal-title":"Stem Cells"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jmoldx.2011.07.008","article-title":"Development of an allele-specific real-time PCR assay for discrimination and quantification of p63 R279H mutation in EEC syndrome","volume":"14","author":"Barbaro","year":"2012","journal-title":"J. Mol. Diagn."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e2227","DOI":"10.1038\/cddis.2016.118","article-title":"Allele-specific silencing of EEC p63 mutant R304W restores p63 transcriptional activity","volume":"7","author":"Novelli","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1007\/BF00947009","article-title":"Ocular manifestations in a father and son with EEC syndrome","volume":"235","author":"Ruprecht","year":"1997","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3633","DOI":"10.1200\/JCO.2011.40.7783","article-title":"Targeting p53 in vivo: A first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer","volume":"30","author":"Lehmann","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1073\/pnas.1201993110","article-title":"APR-246\/PRIMA-1(MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations","volume":"110","author":"Shen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41419-020-2223-8","article-title":"Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1MET\/APR-246","volume":"11","author":"Aberdam","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.arr.2016.06.004","article-title":"The emerging role of Notch pathway in ageing: Focus on the related mechanisms in age-related diseases","volume":"29","author":"Balistreri","year":"2016","journal-title":"Ageing Res. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"15206","DOI":"10.1038\/ncomms15206","article-title":"YAP\/TAZ link cell mechanics to Notch signalling to control epidermal stem cell fate","volume":"8","author":"Totaro","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_56","first-page":"1041","article-title":"Down-regulation of Notch signaling during corneal epithelial proliferation","volume":"14","author":"Djalilian","year":"2008","journal-title":"Mol. Vis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"7476","DOI":"10.1167\/iovs.12-10735","article-title":"Notch inhibition during corneal epithelial wound healing promotes migration","volume":"53","author":"Movahedan","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6598","DOI":"10.1038\/sj.onc.1206758","article-title":"Notch signaling as a therapeutic target in cancer: A new approach to the development of cell fate modifying agents","volume":"22","author":"Nickoloff","year":"2003","journal-title":"Oncogene"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3141","DOI":"10.1158\/1078-0432.CCR-09-2823","article-title":"Targeting Notch to target cancer stem cells","volume":"16","author":"Pannuti","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3977","DOI":"10.1111\/jcmm.17434","article-title":"Analysis and pharmacological modulation of senescence in human epithelial stem cells","volume":"26","author":"Barbaro","year":"2022","journal-title":"J. Cell. Mol. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1182\/bloodadvances.2020003658","article-title":"Using mitochondrial activity to select for potent human hematopoietic stem cells","volume":"5","author":"Qiu","year":"2021","journal-title":"Blood Adv."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.4103\/ijo.IJO_117_19","article-title":"Simple limbal epithelial transplantation (SLET): Review of indications, surgical technique, mechanism, outcomes, limitations, and impact","volume":"67","author":"Shanbhag","year":"2019","journal-title":"Indian J. Ophthalmol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1016\/j.ophtha.2010.11.021","article-title":"Congenital Aniridia Variant: Minimally Abnormal Irides with Severe Limbal Stem Cell Deficiency","volume":"118","author":"Skeens","year":"2011","journal-title":"Ophthalmology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/S0161-6420(02)01081-3","article-title":"Long-term outcomes of keratolimbal allograft for the treatment of severe ocular surface disorders","volume":"109","author":"Ilari","year":"2002","journal-title":"Ophthalmology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1056\/NEJMoa040455","article-title":"Corneal Reconstruction with Tissue-Engineered Cell Sheets Composed of Autologous Oral Mucosal Epithelium","volume":"351","author":"Nishida","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajo.2005.09.003","article-title":"Midterm Results on Ocular Surface Reconstruction Using Cultivated Autologous Oral Mucosal Epithelial Transplantation","volume":"141","author":"Inatomi","year":"2006","journal-title":"Am. J. Ophthalmol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.ajo.2011.03.037","article-title":"Oral Mucosal Graft with Amniotic Membrane Transplantation for Total Limbal Stem Cell Deficiency","volume":"152","author":"Liu","year":"2011","journal-title":"Am. J. Ophthalmol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1167\/iovs.11-7744","article-title":"Cultured Autologous Oral Mucosal Epithelial Cell Sheet (CAOMECS) Transplantation for the Treatment of Corneal Limbal Epithelial Stem Cell Deficiency","volume":"53","author":"Burillon","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3389\/fmed.2020.00043","article-title":"Clinical Outcomes From Cultivated Allogenic Stem Cells vs. Oral Mucosa Epithelial Transplants in Total Bilateral Stem Cells Deficiency","volume":"7","author":"Mozafari","year":"2020","journal-title":"Front. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.exer.2017.06.007","article-title":"Application of CRISPR-Cas9 in eye disease","volume":"161","author":"Wu","year":"2017","journal-title":"Exp. Eye Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1002\/stem.2858","article-title":"Modeling of Aniridia-Related Keratopathy by CRISPR\/Cas9 Genome Editing of Human Limbal Epithelial Cells and Rescue by Recombinant PAX6 Protein","volume":"36","author":"Roux","year":"2018","journal-title":"Stem Cells"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/3\/495\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:22:41Z","timestamp":1760120561000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/3\/495"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,2]]},"references-count":71,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["cells12030495"],"URL":"https:\/\/doi.org\/10.3390\/cells12030495","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,2]]}}}