{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:13:01Z","timestamp":1789776781514,"version":"4.0.1"},"reference-count":37,"publisher":"American Society of Hematology","issue":"9","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,3,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>X-linked chronic granulomatous disease (X-CGD) is a primary immunodeficiency caused by mutations in the CYBB gene, resulting in the inability of phagocytic cells to eliminate infections. To design a lentiviral vector (LV) capable of recapitulating the endogenous regulation and expression of CYBB, a bioinformatics-guided approach was used to elucidate the cognate enhancer elements regulating the native CYBB gene. Using this approach, we analyzed a 600-kilobase topologically associated domain of the CYBB gene and identified endogenous enhancer elements to supplement the CYBB promoter to develop MyeloVec, a physiologically regulated LV for the treatment of X-CGD. When compared with an LV currently in clinical trials for X-CGD, MyeloVec showed improved expression, superior gene transfer to hematopoietic stem and progenitor cells (HSPCs), corrected an X-CGD mouse model leading to complete protection against Burkholderia cepacia infection, and restored healthy donor levels of antimicrobial oxidase activity in neutrophils derived from HSPCs from patients with X-CGD. Our findings validate the bioinformatics-guided design approach and have yielded a novel LV with clinical promise for the treatment of X-CGD.<\/jats:p>","DOI":"10.1182\/blood.2022016074","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T19:57:48Z","timestamp":1667591868000},"page":"1007-1022","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":21,"title":["Lentiviral gene therapy for X-linked chronic granulomatous disease recapitulates endogenous<i>CYBB<\/i>regulation and expression"],"prefix":"10.1182","volume":"141","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4394-9457","authenticated-orcid":false,"given":"Ryan L.","family":"Wong","sequence":"first","affiliation":[{"name":"1Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA"},{"name":"2ImmunoVec, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0028-4985","authenticated-orcid":false,"given":"Sarah","family":"Sackey","sequence":"additional","affiliation":[{"name":"3Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devin","family":"Brown","sequence":"additional","affiliation":[{"name":"3Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shantha","family":"Senadheera","sequence":"additional","affiliation":[{"name":"3Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katelyn","family":"Masiuk","sequence":"additional","affiliation":[{"name":"2ImmunoVec, Los Angeles, CA"},{"name":"3Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9986-4997","authenticated-orcid":false,"given":"Jason P.","family":"Quintos","sequence":"additional","affiliation":[{"name":"2ImmunoVec, Los Angeles, CA"},{"name":"3Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Colindres","sequence":"additional","affiliation":[{"name":"2ImmunoVec, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8370-860X","authenticated-orcid":false,"given":"Luke","family":"Riggan","sequence":"additional","affiliation":[{"name":"2ImmunoVec, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Morgan","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA"},{"name":"4Department of Ophthalmology, Duke University Eye Center, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5874-5775","authenticated-orcid":false,"given":"Harry L.","family":"Malech","sequence":"additional","affiliation":[{"name":"5National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger P.","family":"Hollis","sequence":"additional","affiliation":[{"name":"3Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1840-6087","authenticated-orcid":false,"given":"Donald B.","family":"Kohn","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA"},{"name":"3Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA"},{"name":"6Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA"},{"name":"7Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"6124","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/327717a0","article-title":"The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex","volume":"327","author":"Dinauer","year":"1987","journal-title":"Nature"},{"issue":"3","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/00005792-200005000-00004","article-title":"Genetic, biochemical, and clinical features of chronic granulomatous disease","volume":"79","author":"Segal","year":"2000","journal-title":"Medicine (Baltimore)"},{"issue":"3","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/00005792-200005000-00003","article-title":"Chronic granulomatous disease report on a National Registry of 368 patients","volume":"79","author":"Winkelstein","year":"2000","journal-title":"Medicine (Baltimore)"},{"issue":"8","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1093\/cid\/ciu1154","article-title":"Common severe infections in chronic granulomatous disease","volume":"60","author":"Marciano","year":"2015","journal-title":"Clin Infect Dis"},{"issue":"11","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1038\/gt.2011.65","article-title":"Lineage-and stage-restricted lentiviral vectors for the gene therapy of chronic granulomatous disease","volume":"18","author":"Barde","year":"2011","journal-title":"Gene Ther"},{"issue":"8","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1038\/mt.2014.87","article-title":"Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis","volume":"22","author":"Chiriaco","year":"2014","journal-title":"Mol Ther"},{"issue":"10","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1038\/gt.2011.167","article-title":"Physiological regulation of transgene expression by a lentiviral vector containing the A2UCOE linked to a myeloid promoter","volume":"19","author":"Brendel","year":"2012","journal-title":"Gene Ther"},{"issue":"2","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41591-019-0735-5","article-title":"Lentiviral gene therapy for X-linked chronic granulomatous disease","volume":"26","author":"Kohn","year":"2020","journal-title":"Nat Med"},{"issue":"1","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/mt.2010.226","article-title":"Biochemical correction of X-CGD by a novel chimeric promoter regulating high levels of transgene expression in myeloid cells","volume":"19","author":"Santilli","year":"2011","journal-title":"Mol Ther"},{"issue":"19","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1182\/blood.2020008503","article-title":"Enhanced homology-directed repair for highly efficient gene editing in hematopoietic stem\/progenitor cells","volume":"137","author":"De Ravin","year":"2021","journal-title":"Blood"},{"issue":"6","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/s41434-021-00251-z","article-title":"Correction of X-CGD patient HSPCs by targeted CYBB cDNA insertion using CRISPR\/Cas9 with 53BP1 inhibition for enhanced homology-directed repair","volume":"28","author":"Sweeney","year":"2021","journal-title":"Gene Ther"},{"issue":"11","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"8463","DOI":"10.1128\/JVI.72.11.8463-8471.1998","article-title":"A third-generation lentivirus vector with a conditional packaging system","volume":"72","author":"Dull","year":"1998","journal-title":"J\u00a0Virol"},{"issue":"1","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jviromet.2011.06.019","article-title":"Highly efficient large-scale lentiviral vector concentration by tandem tangential flow filtration","volume":"177","author":"Cooper","year":"2011","journal-title":"J\u00a0Virol Methods"},{"issue":"7414","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","author":"Dunham","year":"2012","journal-title":"Nature"},{"issue":"D1","key":"2023030216272613300_","first-page":"D682","article-title":"Ensembl 2020","volume":"48","author":"Yates","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"170113","DOI":"10.1038\/sdata.2017.113","article-title":"The FANTOM5 collection, a data series underpinning mammalian transcriptome atlases in diverse cell types","volume":"4","author":"Kawaji","year":"2017","journal-title":"Sci Data"},{"issue":"suppl 1","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1093\/nar\/gkl822","article-title":"VISTA Enhancer Browser - a database of tissue-specific human enhancers","volume":"35","author":"Visel","year":"2007","journal-title":"Nucleic Acids Res"},{"issue":"8","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1182\/blood-2005-08-024976","article-title":"Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity","volume":"108","author":"Modlich","year":"2006","journal-title":"Blood"},{"issue":"12","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"3383","DOI":"10.1016\/j.ymthe.2021.06.017","article-title":"Predicting genotoxicity of viral vectors for stem cell gene therapy using gene expression-based machine learning","volume":"29","author":"Schwarzer","year":"2021","journal-title":"Mol Ther"},{"issue":"2","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1006\/bcmd.2002.0513","article-title":"Surface antigen changes during normal neutrophilic development: A critical review","volume":"28","author":"Elghetany","year":"2002","journal-title":"Blood Cells Mol Dis"},{"issue":"2","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.ymthe.2016.11.012","article-title":"Targeted repair of CYBB in X-CGD iPSCs requires retention of intronic sequences for expression and functional correction","volume":"25","author":"Sweeney","year":"2017","journal-title":"Mol Ther"},{"issue":"11","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/sj.gt.3302270","article-title":"Pois(s)on - it\u2019s a question of dose","volume":"11","author":"Fehse","year":"2004","journal-title":"Gene Ther"},{"issue":"5","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/gt.2010.163","article-title":"Quantification of lentiviral vector copy numbers in individual hematopoietic colony-forming cells shows vector dose-dependent effects on the frequency and level of transduction","volume":"18","author":"Charrier","year":"2011","journal-title":"Gene Ther"},{"issue":"9","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1093\/nar\/24.9.1787","article-title":"The human ubiquitin C promoter directs high ubiquitous expression of transgenes in mice","volume":"24","author":"Schorpp","year":"1996","journal-title":"Nucleic Acids Res"},{"issue":"1-2","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.jim.2012.08.005","article-title":"Humanised mice have functional human neutrophils","volume":"385","author":"Coughlan","year":"2012","journal-title":"J\u00a0Immunol Methods"},{"issue":"15","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"3431","DOI":"10.1182\/blood-2011-12-398024","article-title":"Distinct but phenotypically heterogeneous human cell populations produce rapid recovery of platelets and neutrophils after transplantation","volume":"119","author":"Cheung","year":"2012","journal-title":"Blood"},{"issue":"suppl 2","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1093\/nar\/gki376","article-title":"JCat: A novel tool to adapt codon usage of a target gene to its potential expression host","volume":"33","author":"Grote","year":"2005","journal-title":"Nucleic Acids Res"},{"issue":"9","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"4968","DOI":"10.4049\/jimmunol.161.9.4968","article-title":"Nicotinamide-adenine dinucleotide phosphate oxidase assembly and activation in\u00a0EBV-transformed B lymphoblastoid cell lines of normal and chronic granulomatous disease patients","volume":"161","author":"Dusi","year":"1998","journal-title":"J\u00a0Immunol"},{"issue":"7","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.4049\/jimmunol.140.7.2334","article-title":"The superoxide generating system of B cell lines. Structural homology with the phagocytic oxidase and triggering via surface Ig","volume":"140","author":"Maly","year":"1988","journal-title":"J\u00a0Immunol"},{"issue":"3","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.jaci.2014.07.012","article-title":"Defective B-cell proliferation and maintenance of long-term memory in patients with chronic granulomatous disease","volume":"135","author":"Cotugno","year":"2015","journal-title":"J\u00a0Allergy Clin Immunol"},{"issue":"1","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.ymthe.2019.09.020","article-title":"Improved titer and gene transfer by lentiviral vectors using novel, small \u03b2-globin locus control region elements","volume":"28","author":"Morgan","year":"2019","journal-title":"Mol Ther"},{"issue":"2020","key":"2023030216272613300_","first-page":"1","article-title":"\u03b2-Globin lentiviral vectors have reduced titers due to incomplete vector RNA genomes and lowered virion production","volume":"16","author":"Han","year":"2020","journal-title":"Stem Cell Rep"},{"key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.omtm.2020.04.006","article-title":"Creating\u00a0new \u03b2-globin-expressing lentiviral vectors by high-resolution mapping of locus\u00a0control region enhancer sequences","volume":"17","author":"Morgan","year":"2020","journal-title":"Mol\u00a0Ther Methods Clin Dev"},{"issue":"12","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"3738","DOI":"10.1182\/blood.V97.12.3738","article-title":"Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease","volume":"97","author":"Dinauer","year":"2001","journal-title":"Blood"},{"issue":"9","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1038\/mt.2009.134","article-title":"Cell-intrinsic and vector-related properties cooperate to determine the incidence and consequences of insertional mutagenesis","volume":"17","author":"Kustikova","year":"2009","journal-title":"Mol Ther"},{"issue":"1","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/mt.2010.232","article-title":"Gene therapy of chronic granulomatous disease: the engraftment dilemma","volume":"19","author":"Grez","year":"2011","journal-title":"Mol Ther"},{"issue":"11","key":"2023030216272613300_","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1182\/blood-2011-01-330050","article-title":"Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells","volume":"118","author":"Yahata","year":"2011","journal-title":"Blood"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/141\/9\/1007\/2036415\/blood_bld-2022-016074-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/141\/9\/1007\/2036415\/blood_bld-2022-016074-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T05:11:54Z","timestamp":1678511514000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/141\/9\/1007\/487021\/Lentiviral-gene-therapy-for-X-linked-chronic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,2]]},"references-count":37,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2023,3,2]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2022016074","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,2]]}}}