{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:16:35Z","timestamp":1792034195525,"version":"4.4.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>\n                    Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma. There is no definitive therapy for any form of EB. Intermediate junctional EB (JEB) caused by mutations in the gene\n                    <jats:italic>LAMB3<\/jats:italic>\n                    has been the first genetic skin disease successfully tackled by\n                    <jats:italic>ex vivo<\/jats:italic>\n                    gene therapy. Here, we present a multicenter, open-label, uncontrolled phase II\/III study that aims at confirming the efficacy of Hologene 5, a graft consisting of cultured transgenic keratinocytes and epidermal stem cells and meant to combine cell and gene therapy for the treatment of\n                    <jats:italic>LAMB3<\/jats:italic>\n                    -related JEB. Autologous clonogenic keratinocytes will be isolated from patients\u2019 skin biopsies, genetically corrected with a gamma-retroviral vector (\u03b3RV) carrying the full-length human\n                    <jats:italic>LAMB3<\/jats:italic>\n                    cDNA and plated onto a fibrin support (144cm\n                    <jats:sup>2<\/jats:sup>\n                    ). The transgenic epidermis will be transplanted onto surgically prepared selected skin areas of at least six JEB patients (four pediatric and two adults). Evaluation of clinical efficacy will include, as primary endpoint, a combination of clinical parameters, such as percentage of re-epithelialization, cellular, molecular, and functional parameters, mechanical stress tests, and patient-reported outcome (PRO), up to 12months after transplantation. Safety and further efficacy endpoints will also be assessed during the clinical trial and for additional 15years in an interventional non-pharmacological follow-up study. If successful, this clinical trial would provide a therapeutic option for skin lesions of JEB patients with\n                    <jats:italic>LAMB3<\/jats:italic>\n                    mutations and pave the way to a combined cell and gene therapy platform tackling other forms of EB and different genodermatoses.\n                  <\/jats:p>\n                  <jats:p>Clinical Trial Registration: EudraCT Number: 2018-000261-36.<\/jats:p>","DOI":"10.3389\/fgene.2021.705019","type":"journal-article","created":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T21:01:57Z","timestamp":1630702917000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Hologene 5: A Phase II\/III Clinical Trial of Combined Cell and Gene Therapy of Junctional Epidermolysis Bullosa"],"prefix":"10.3389","volume":"12","author":[{"given":"Laura","family":"De Rosa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Enzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Zardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Bodemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Magnoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holm","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"De Luca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/s41572-020-0210-0","article-title":"Epidermolysis bullosa","volume":"6","author":"Bardhan","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1016\/j.jid.2016.10.038","article-title":"Closure of a large chronic wound through transplantation of gene-corrected epidermal stem cells","volume":"137","author":"Bauer","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"244","DOI":"10.4103\/idoj.IDOJ_287_18","article-title":"Newer treatment modalities in Epidermolysis Bullosa","volume":"10","author":"Bruckner-Tuderman","year":"2019","journal-title":"Indian Dermatol. Online J."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1038\/labinvest.3700164","article-title":"Analysis of the LAMB3 gene in a junctional epidermolysis bullosa patient reveals exonic splicing and allele-specific nonsense-mediated mRNA decay","volume":"84","author":"Buchroithner","year":"2004","journal-title":"Lab. Investig."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/gt.2013.18","article-title":"Self-inactivating MLV vectors have a reduced genotoxic profile in human epidermal keratinocytes","volume":"20","author":"Cavazza","year":"2013","journal-title":"Gene Ther."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1038\/s41556-019-0344-z","article-title":"Advances in stem cell research and therapeutic development","volume":"21","author":"De Luca","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"45","DOI":"10.2217\/17460751.1.1.45","article-title":"Regeneration of squamous epithelia from stem cells of cultured grafts","volume":"1","author":"De Luca","year":"2006","journal-title":"Regen. Med."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.stemcr.2013.11.001","article-title":"Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa","volume":"2","author":"De Rosa","year":"2014","journal-title":"Stem Cell Rep."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"a035667","DOI":"10.1101\/cshperspect.a035667","article-title":"Toward combined cell and gene therapy for genodermatoses","volume":"12","author":"De Rosa","year":"2020","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"e130554","DOI":"10.1172\/jci.insight.130554","article-title":"Phase 1\/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa","volume":"4","author":"Eichstadt","year":"2019","journal-title":"JCI Insight"},{"key":"ref11","year":"2019"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/1750-1172-5-12","article-title":"Inherited epidermolysis bullosa","volume":"5","author":"Fine","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1016\/j.jaad.2012.01.045","article-title":"Squamous cell carcinoma and junctional epidermolysis bullosa","volume":"66","author":"Fine","year":"2012","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1016\/j.jaad.2014.01.903","article-title":"Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification","volume":"70","author":"Fine","year":"2014","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.jaad.2008.09.035","article-title":"Epidermolysis bullosa and the risk of life-threatening cancers: the national EB registry experience, 1986-2006","volume":"60","author":"Fine","year":"2009","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/j.jpeds.2007.06.039","article-title":"Cause-specific risks of childhood death in inherited epidermolysis bullosa","volume":"152","author":"Fine","year":"2008","journal-title":"J. Pediatr."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1111\/j.1365-2133.2009.09347.x","article-title":"Quality of life evaluation in epidermolysis bullosa (EB) through the development of the QOLEB questionnaire: an EB-specific quality of life instrument","volume":"161","author":"Frew","year":"2009","journal-title":"Br. J. Dermatol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1056\/NEJM198408163110706","article-title":"Permanent coverage of large burn wounds with autologous cultured human epithelium","volume":"311","author":"Gallico","year":"1984","journal-title":"N. Engl. J. Med."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1186\/s12916-014-0178-2","article-title":"Pain care for patients with epidermolysis bullosa: best care practice guidelines","volume":"12","author":"Goldschneider","year":"2014","journal-title":"BMC Med."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1016\/j.jid.2016.06.609","article-title":"Genotype, clinical course, and therapeutic decision-making in 76 infants with severe generalized junctional epidermolysis bullosa","volume":"136","author":"Hammersen","year":"2016","journal-title":"J. Invest. Dermatol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1159\/000499906","article-title":"Attenuation of severe generalized junctional epidermolysis bullosa by systemic treatment with gentamicin","volume":"235","author":"Hammersen","year":"2019","journal-title":"Dermatology"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1111\/bjd.18921","article-title":"Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility","volume":"183","author":"Has","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/nature24487","article-title":"Regeneration of the entire human epidermis using transgenic stem cells","volume":"551","author":"Hirsch","year":"2017","journal-title":"Nature"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"3143","DOI":"10.1172\/JCI35798","article-title":"Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients","volume":"118","author":"Howe","year":"2008","journal-title":"J. Clin. Invest."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"135","DOI":"10.4161\/cam.22418","article-title":"Laminin 332 in junctional epidermolysis bullosa","volume":"7","author":"Kiritsi","year":"2013","journal-title":"Cell Adhes. Migr."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1097\/01.TP.0000144325.01925.BE","article-title":"Haematopoietic stem cell transplantation and subsequent 80% skin exchange by grafts from the same donor in a patient with Herlitz disease","volume":"79","author":"Kopp","year":"2005","journal-title":"Transplantation"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1016\/j.ymthe.2020.03.006","article-title":"Gentamicin induces Laminin 332 and improves wound healing in junctional epidermolysis bullosa patients with nonsense mutations","volume":"28","author":"Kwong","year":"2020","journal-title":"Mol. Ther."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"89.e81-13","DOI":"10.1016\/j.jaad.2013.09.041","article-title":"Development, reliability, and validity of a novel epidermolysis bullosa disease activity and scarring index (EBDASI)","volume":"70","author":"Loh","year":"2014","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1111\/j.1468-3083.2004.00968.x","article-title":"Increased risk of squamous cell carcinoma in junctional epidermolysis bullosa","volume":"18","author":"Mallipeddi","year":"2004","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1038\/nm1504","article-title":"Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells","volume":"12","author":"Mavilio","year":"2006","journal-title":"Nat. Med."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1046\/j.1365-2133.1998.02377.x","article-title":"E210K mutation in the gene encoding the beta3 chain of laminin-5 (LAMB3) is predictive of a phenotype of generalized atrophic benign epidermolysis bullosa","volume":"139","author":"Mellerio","year":"1998","journal-title":"Br. J. Dermatol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/s13023-020-01403-x","article-title":"Emergency management in epidermolysis bullosa: consensus clinical recommendations from the European reference network for rare skin diseases","volume":"15","author":"Mellerio","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s13023-016-0489-9","article-title":"Inherited epidermolysis bullosa and squamous cell carcinoma: a systematic review of 117 cases","volume":"11","author":"Montaudie","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"553","DOI":"10.2217\/rme.13.43","article-title":"Biological parameters determining the clinical outcome of autologous cultures of limbal stem cells","volume":"8","author":"Pellegrini","year":"2013","journal-title":"Regen. Med."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1097\/00007890-199909270-00021","article-title":"The control of epidermal stem cells (holoclones) in the treatment of massive full-thickness burns with autologous keratinocytes cultured on fibrin","volume":"68","author":"Pellegrini","year":"1999","journal-title":"Transplantation"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1016\/S0140-6736(96)11188-0","article-title":"Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium","volume":"349","author":"Pellegrini","year":"1997","journal-title":"Lancet"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1111\/j.0022-202X.2004.23302.x","article-title":"Laminin-5 mutational analysis in an Italian cohort of patients with junctional epidermolysis bullosa","volume":"123","author":"Posteraro","year":"2004","journal-title":"J. Invest. Dermatol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1089\/hum.2010.023","article-title":"Long-term type VII collagen restoration to human epidermolysis bullosa skin tissue","volume":"21","author":"Siprashvili","year":"2010","journal-title":"Hum. Gene Ther."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1808","DOI":"10.1001\/jama.2016.15588","article-title":"Safety and wound outcomes following genetically corrected autologous epidermal grafts in patients With recessive dystrophic epidermolysis bullosa","volume":"316","author":"Siprashvili","year":"2016","journal-title":"JAMA"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1007\/s11684-011-0159-1","article-title":"Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity","volume":"5","author":"Wu","year":"2011","journal-title":"Front. Med."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1016\/j.jaad.2010.07.006","article-title":"Risk of squamous cell carcinoma in junctional epidermolysis bullosa, non-Herlitz type: report of 7 cases and a review of the literature","volume":"65","author":"Yuen","year":"2011","journal-title":"J. Am. Acad. Dermatol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.705019\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T21:01:58Z","timestamp":1630702918000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.705019\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,1]]},"references-count":41,"alternative-id":["10.3389\/fgene.2021.705019"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2021.705019","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,1]]},"article-number":"705019"}}