{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:10:54Z","timestamp":1787008254440,"version":"build-2736575974"},"reference-count":36,"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                    Replacing a faulty gene with a correct copy has become a viable therapeutic option as a result of recent progress in gene editing protocols. Targeted integration of therapeutic genes in hematopoietic stem cells has been achieved for multiple genes using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)\/Cas9 system and Adeno-Associated Virus (AAV) to carry a donor template. Although this is a promising strategy to correct genetic blood disorders, it is associated with toxicity and loss of function in CD34\n                    <jats:sup>+<\/jats:sup>\n                    hematopoietic stem and progenitor cells, which has hampered clinical application. Balancing the maximum achievable correction against deleterious effects on the cells is critical. However, multiple factors are known to contribute, and the optimization process is laborious and not always clearly defined. We have developed a flexible multidimensional Response Surface Methodology approach for optimization of gene correction. Using this approach, we could rapidly investigate and select editing conditions for CD34\n                    <jats:sup>+<\/jats:sup>\n                    cells with the best possible balance between correction and cell\/colony-forming unit (CFU) loss in a parsimonious one-shot experiment. This method revealed that using relatively low doses of AAV2\/6 and CRISPR\/Cas9 ribonucleoprotein complex, we can preserve the fitness of CD34\n                    <jats:sup>+<\/jats:sup>\n                    cells and, at the same time, achieve high levels of targeted gene insertion. We then used these optimized editing conditions for the correction of p67\n                    <jats:sup>phox<\/jats:sup>\n                    -deficient chronic granulomatous disease (CGD), an autosomal recessive disorder of blood phagocytic cells resulting in severe recurrent bacterial and fungal infections and achieved rescue of p67\n                    <jats:sup>phox<\/jats:sup>\n                    expression and functional correction of CD34\n                    <jats:sup>+<\/jats:sup>\n                    -derived neutrophils from a CGD patient.\n                  <\/jats:p>","DOI":"10.1089\/hum.2023.114","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T02:39:16Z","timestamp":1702003156000},"page":"298-312","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Multidimensional Response Surface Methodology for the Development of a Gene Editing Protocol for p67\n                    <sup>phox<\/sup>\n                    -Deficient Chronic Granulomatous Disease"],"prefix":"10.1177","volume":"35","author":[{"given":"Thomas E.","family":"Whittaker","sequence":"first","affiliation":[{"name":"Infection, Immunity, and Inflammation Research and Teaching Department, UCL, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shefta E.","family":"Moula","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Research and Teaching Department, UCL, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer","family":"Bahal","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Research and Teaching Department, UCL, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faris Ghalib","family":"Bakri","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Jordan University Hospital, Amman, Jordan."},{"name":"Infectious Diseases and Vaccine Center, University of Jordan, Amman, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wail Ahmad","family":"Hayajneh","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, Jordan University of Science &amp; Technology, Irbid, Jordan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammar Khaled","family":"Daoud","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Internal Medicine, Jordan University of Science &amp; Technology, Irbid, Jordan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asma","family":"Naseem","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Research and Teaching Department, UCL, 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 Research and Teaching Department, UCL, 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 Research and Teaching Department, UCL, 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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1776-1984","authenticated-orcid":false,"given":"Giorgia","family":"Santilli","sequence":"additional","affiliation":[{"name":"Infection, Immunity, and Inflammation Research and Teaching Department, UCL, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2024,4,16]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/jpids\/piy008"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu1154"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1084\/JEM.20161382"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.7554\/ELIFE.76387"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.639226"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1007097"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/FPED.2020.00327"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/STEM.1691"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2021.648951"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41434-021-00251-z"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aah3480"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/S41591-019-0735-5"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41434-020-0164-6"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2016001214"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.22.12133"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1182\/BLOOD.V89.5.1754"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/MT.2014.195"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.12.009"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1388"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/MT.2010.232"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.add8643"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40291-022-00618-x"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.3389\/FGEED.2020.613252"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/J.YMTHE.2021.09.001"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/J.STEM.2019.02.019"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20792-y"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/J.BBMT.2011.01.011"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1080\/00224065.2004.11980252"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/WICS.73"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1089\/hgtb.2011.034"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1214\/aoms\/1177707047"},{"issue":"4","key":"e_1_3_6_33_2","first-page":"34","article-title":"Preclinical safety and feasibility study of a CRISPR\/Cas9 gene editing platform to treat Wiskott Aldrich syndrome","volume":"30","author":"Naseem A","year":"2022","unstructured":"Naseem A, , Rai R, , Turchiano G, et al. Preclinical safety and feasibility study of a CRISPR\/Cas9 gene editing platform to treat Wiskott Aldrich syndrome. Mol Ther, 2022; 30(4):34.","journal-title":"Mol Ther"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/S41467-020-17626-2"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/NATURE20134"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0551-y"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.18609\/CGTI.2018.016"}],"container-title":["Human Gene Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/hum.2023.114","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2023.114","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2023.114","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:57:15Z","timestamp":1777449435000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/hum.2023.114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4]]},"references-count":36,"journal-issue":{"issue":"7-8","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1089\/hum.2023.114"],"URL":"https:\/\/doi.org\/10.1089\/hum.2023.114","relation":{},"ISSN":["1043-0342","1557-7422"],"issn-type":[{"value":"1043-0342","type":"print"},{"value":"1557-7422","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4]]}}}