{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T04:16:04Z","timestamp":1790050564146,"version":"4.0.1"},"reference-count":49,"publisher":"SAGE Publications","issue":"7-8","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:p>\n                    Interleukin 7 Receptor alpha Severe Combined Immunodeficiency (IL7R-SCID) is a life-threatening disorder caused by homozygous mutations in the\n                    <jats:italic toggle=\"yes\">IL7RA<\/jats:italic>\n                    gene. Defective IL7R expression in humans hampers T cell precursors' proliferation and differentiation during lymphopoiesis resulting in the absence of T cells in newborns, who succumb to severe infections and death early after birth. Previous attempts to tackle IL7R-SCID by viral gene therapy have shown that unregulated IL7R expression predisposes to leukemia, suggesting the application of targeted gene editing to insert a correct copy of the\n                    <jats:italic toggle=\"yes\">IL7RA<\/jats:italic>\n                    gene in its genomic locus and mediate its physiological expression as a more feasible therapeutic approach. To this aim, we have first developed a CRISPR\/Cas9-based IL7R-SCID disease modeling system that recapitulates the disease phenotype in primary human T cells and hematopoietic stem and progenitor cells (HSPCs). Then, we have designed a knockin strategy that targets\n                    <jats:italic toggle=\"yes\">IL7RA<\/jats:italic>\n                    exon 1 and introduces through homology-directed repair a corrective, promoterless IL7RA cDNA followed by a reporter cassette through AAV6 transduction. Targeted integration of the corrective cassette in primary T cells restored IL7R expression and rescued functional downstream IL7R signaling. When applied to HSPCs further induced to differentiate into T cells in an Artificial Thymic Organoid system, our gene editing strategy overcame the T cell developmental block observed in IL7R-SCID patients, while promoting full maturation of T cells with physiological and developmentally regulated IL7R expression. Finally, genotoxicity assessment of the CRISPR\/Cas9 platform in HSPCs using biased and unbiased technologies confirmed the safety of the strategy, paving the way for a new, efficient, and safe therapeutic option for IL7R-SCID patients.\n                  <\/jats:p>","DOI":"10.1089\/hum.2023.100","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T07:20:07Z","timestamp":1705908007000},"page":"269-283","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":15,"title":["CRISPR\/Cas9-Based Disease Modeling and Functional Correction of Interleukin 7 Receptor Alpha Severe Combined Immunodeficiency in T-Lymphocytes and Hematopoietic Stem Cells"],"prefix":"10.1177","volume":"35","author":[{"given":"Rajeev","family":"Rai","sequence":"first","affiliation":[{"name":"Infection, Immunity, and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zohar","family":"Steinberg","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Romito","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Zinghirino","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ting","family":"Hu","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"White","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asma","family":"Naseem","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6097-6115","authenticated-orcid":false,"given":"Adrian J.","family":"Thrasher","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."},{"name":"NIHR Great Ormond Street Hospital Biomedical Research Center, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giandomenico","family":"Turchiano","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4735-2121","authenticated-orcid":false,"given":"Alessia","family":"Cavazza","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."},{"name":"NIHR Great Ormond Street Hospital Biomedical Research Center, London, United Kingdom."},{"name":"Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, 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