{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:04:12Z","timestamp":1787508252813,"version":"build-2736575974"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T00:00:00Z","timestamp":1605744000000},"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. Immunol."],"abstract":"<jats:p>\n                    Genetic defects in recombination activating genes (RAG) 1 and 2 cause a broad spectrum of severe immune defects ranging from early severe and repeated infections to inflammation and autoimmune manifestations. A correlation between\n                    <jats:italic>in vitro<\/jats:italic>\n                    recombination activity and immune phenotype has been described. Hematopoietic cell transplantation is the treatment of care; however, the availability of next generation sequencing and whole genome sequencing has allowed the identification of novel genetic RAG variants in immunodeficient patients at various ages, raising therapeutic questions. This review addresses the recent advances of novel therapeutic approaches for RAG deficiency. As conventional myeloablative conditioning regimens are associated with acute toxicities and transplanted-related mortality, innovative minimal conditioning regimens based on the use of monoclonal antibodies are now emerging and show promising results. To overcome shortage of compatible donors, gene therapy has been developed in various RAG preclinical models. Overall, the transplantation of autologous gene corrected hematopoietic precursors and the use of non-genotoxic conditioning will open a new era, offering a cure to an increasing number of RAG patients regardless of donor availability and severity of clinical conditions.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2020.607926","type":"journal-article","created":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T03:30:03Z","timestamp":1605756603000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Innovative Cell-Based Therapies and Conditioning to Cure RAG Deficiency"],"prefix":"10.3389","volume":"11","author":[{"given":"Anna","family":"Villa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Capo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carmina","family":"Castiello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,11,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1146\/annurev-genet-110410-132552","article-title":"V(D)J Recombination: Mechanisms of Initiation","volume":"45","author":"Schatz","year":"2011","journal-title":"Annu Rev Genet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5284.97","article-title":"RAG mutations in human B cell-negative SCID","volume":"274","author":"Schwarz","year":"1996","journal-title":"Sci (80- )"},{"key":"B3","doi-asserted-by":"publisher","first-page":"15061","DOI":"10.1038\/nrdp.2015.61","article-title":"Severe combined immunodeficiencies and related disorders","volume":"1","author":"Fischer","year":"2015","journal-title":"Nat Rev Dis Prim"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81448-8","article-title":"Partial V(D)J recombination activity leads to omenn syndrome","volume":"93","author":"Villa","year":"1998","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.28","article-title":"Human RAG mutations: Biochemistry and clinical implications","volume":"16","author":"Notarangelo","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151116","article-title":"Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects","volume":"213","author":"Rigoni","year":"2016","journal-title":"J Exp Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.04.005","article-title":"Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn syndrome","author":"Rigoni","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091928","article-title":"Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome","volume":"207","author":"Cassani","year":"2010","journal-title":"J Exp Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091927","article-title":"Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency","volume":"207","author":"Walter","year":"2010","journal-title":"J Exp Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/BLOOD.2019000923","article-title":"Immune dysregulation in patients with RAG deficiency and other forms of combined immune deficiency","volume":"135","author":"Delmonte","year":"2020","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1111\/imr.12713","article-title":"RAG gene defects at the verge of immunodeficiency and immune dysregulation","volume":"287","author":"Villa","year":"2019","journal-title":"Immunol Rev"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.04.027","article-title":"Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype","volume":"143","author":"Tirosh","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2019.02.038","article-title":"Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency","volume":"7","author":"Farmer","year":"2019","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2020.1670060","article-title":"Approaches to patients with variants in RAG genes: from diagnosis to timely treatment","volume":"15","author":"Bulkhi","year":"2019","journal-title":"Expert Rev Clin Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-018-0537-4","article-title":"RAG Deficiency: Two Genes, Many Diseases","volume":"38","author":"Delmonte","year":"2018","journal-title":"J Clin Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.06.032","article-title":"Expanding the spectrum of recombination-activating gene 1 deficiency: A family with early-onset autoimmunity","volume":"132","author":"Henderson","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25178","article-title":"A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection","volume":"115","author":"De Villartay","year":"2005","journal-title":"J Clin Invest"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25221","article-title":"A variant of SCID with specific immune responses and predominance of \u03b3\u03b4 T cells","volume":"115","author":"Ehl","year":"2005","journal-title":"J Clin Invest"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80477","article-title":"Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency","volume":"125","author":"Walter","year":"2015","journal-title":"J Clin Invest"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa073966","article-title":"An immunodeficiency disease with RAG mutations and granulomas","volume":"358","author":"Schuetz","year":"2008","journal-title":"N Engl J Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw675","article-title":"Cutaneous and visceral chronic granulomatous disease triggered by a rubella virus vaccine strain in children with primary immunodeficiencies","volume":"64","author":"Neven","year":"2017","journal-title":"Clin Infect Dis"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-329052","article-title":"Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations","volume":"117","author":"Kuijpers","year":"2011","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-015-0146-4","article-title":"RAG1 Deficiency May Present Clinically as Selective IgA Deficiency","volume":"35","author":"Kato","year":"2015","journal-title":"J Clin Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0133220","article-title":"Leaky RAG deficiency in adult patients with impaired antibody production against bacterial polysaccharide antigens","volume":"10","author":"Geier","year":"2015","journal-title":"PloS One"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2012.06.012","article-title":"A novel homozygous mutation in recombination activating gene 2 in 2 relatives with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome","volume":"130","author":"Chou","year":"2012","journal-title":"J Allergy Clin Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30928","article-title":"A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome","volume":"117","author":"Marrella","year":"2007","journal-title":"J Clin Invest"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30513","article-title":"Homeostatically proliferating CD4+ T cells are involved in the pathogenesis of an Omenn syndrome murine model","volume":"117","author":"Khiong","year":"2007","journal-title":"J Clin Invest"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-07-165167","article-title":"Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation","volume":"113","author":"Giblin","year":"2009","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-12-820985","article-title":"Hypomorphic Rag1 mutations alter the preimmune repertoire at early stages of lymphoid development","volume":"132","author":"Ott de Bruin","year":"2018","journal-title":"Blood"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2016.1228517","article-title":"RAGs and BUGS: An alliance for autoimmunity","volume":"7","author":"Rigoni","year":"2016","journal-title":"Gut Microbes"},{"key":"B31","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1093\/bmb\/ldaa017","article-title":"The challenges presented by haematopoietic stem cell transplantation in children with primary immunodeficiency","volume":"135","author":"Gennery","year":"2020","journal-title":"Br Med Bull"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/s11882-019-0883-1","article-title":"Conditioning Regimens for Hematopoietic Cell Transplantation in Primary Immunodeficiency","volume":"19","author":"Lum","year":"2019","journal-title":"Curr Allergy Asthma Rep"},{"key":"B33","unstructured":"ClinicalTrials.govAMG 191 Antibody Targeting Conditioning in SCID Patients"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2008.10.030","article-title":"Long-term outcomes of nonconditioned patients with severe combined immunodeficiency transplanted with HLA-identical or haploidentical bone marrow depleted of T cells with anti-CD6 mAb","volume":"122","author":"Patel","year":"2008","journal-title":"J Allergy Clin Immunol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.bbmt.2019.08.018","article-title":"Prospective Study of a Novel, Radiation-Free, Reduced-Intensity Bone Marrow Transplantation Platform for Primary Immunodeficiency Diseases","volume":"26","author":"Dimitrova","year":"2020","journal-title":"Biol Blood Marrow Transplant"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/petr.12309","article-title":"Cowan MJ. A trial of plerixafor adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency","volume":"18","author":"Dvorak","year":"2014","journal-title":"Pediatr Transplant"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/petr.12310","article-title":"Cowan MJ. A trial of alemtuzumab adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency","volume":"18","author":"Dvorak","year":"2014","journal-title":"Pediatr Transplant"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60945-4","article-title":"Haemopoietic stem-cell transplantation with antibody-based minimal-intensity conditioning: a phase 1\/2 study","volume":"374","author":"Straathof","year":"2009","journal-title":"Lancet"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-01-476432","article-title":"SCID patients with ARTEMIS vs RAG deficiencies following HCT: Increased risk of late toxicity in ARTEMIS-deficient SCID","volume":"123","author":"Schuetz","year":"2014","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-018-0540-9","article-title":"Long-Term Health Outcome and Quality of Life Post-HSCT for IL7R\u03b1-, Artemis-, RAG1- and RAG2-Deficient Severe Combined Immunodeficiency: a Single Center Report","volume":"38","author":"Abd Hamid","year":"2018","journal-title":"J Clin Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1404588","article-title":"A modified \u03b3-retrovirus vector for X-linked severe combined immunodeficiency","volume":"371","author":"Hacein-Bey-Abina","year":"2014","journal-title":"N Engl J Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-03-840702","article-title":"SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery","volume":"132","author":"Haddad","year":"2018","journal-title":"Blood"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2016.12.619","article-title":"Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Stem Cell Transplantation (HCT) for Severe Combined Immunodeficiency Patients: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium","volume":"23","author":"Heimall","year":"2017","journal-title":"Biol Blood Marrow Transplant"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1401177","article-title":"Transplantation outcomes for severe combined immunodeficiency, 2000-2009","volume":"371","author":"Pai","year":"2014","journal-title":"N Engl J Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00295","article-title":"Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Diseases: Current Status and Future Perspectives","volume":"7","author":"Castagnoli","year":"2019","journal-title":"Front Pediatr"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00373","article-title":"Universal Newborn Screening for Severe Combined Immunodeficiency (SCID)","volume":"7","author":"van der Burg","year":"2019","journal-title":"Front Pediatr"},{"key":"B47","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1016\/j.stem.2019.06.003","article-title":"Stress-Induced Changes in Bone Marrow Stromal Cell Populations Revealed through Single-Cell Protein Expression Mapping","volume":"25","author":"Severe","year":"2019","journal-title":"Cell Stem Cell"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3346","article-title":"Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal","volume":"18","author":"Pietras","year":"2016","journal-title":"Nat Cell Biol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-01-0061","article-title":"Competition within the early B-cell compartment conditions B-cell reconstitution after hematopoietic stem cell transplantation in nonirradiated recipients","volume":"108","author":"Liu","year":"2006","journal-title":"Blood"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1126\/science.1149726","article-title":"Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches","volume":"318","author":"Czechowicz","year":"2007","journal-title":"Sci (80- )"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-07-295949","article-title":"Antibody targeting KIT as pretransplantation conditioning in immunocompetent mice","volume":"116","author":"Xue","year":"2010","journal-title":"Blood"},{"key":"B52","doi-asserted-by":"publisher","first-page":"351ra105","DOI":"10.1126\/scitranslmed.aae0501","article-title":"Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy","volume":"8","author":"Chhabra","year":"2016","journal-title":"Sci Transl Med"},{"key":"B53","doi-asserted-by":"publisher","first-page":"S92","DOI":"10.1016\/j.bbmt.2018.12.172","article-title":"Toxicity-Free Hematopoietic Stem Cell Engraftment Achieved with Anti-CD117 Monoclonal Antibody Conditioning","volume":"25","author":"Agarwal","year":"2019","journal-title":"Biol Blood Marrow Transplant"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2014.10.010","article-title":"Outcomes of Donor Lymphocyte Infusion for Treatment of Mixed Donor Chimerism after a Reduced-Intensity Preparative Regimen for Pediatric Patients with Nonmalignant Diseases","volume":"21","author":"Haines","year":"2015","journal-title":"Biol Blood Marrow Transplant"},{"key":"B55","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1038\/s41467-018-08201-x","article-title":"Selective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation","volume":"10","author":"Czechowicz","year":"2019","journal-title":"Nat Commun"},{"key":"B56","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/s41467-018-08202-w","article-title":"Hematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation","volume":"10","author":"Li","year":"2019","journal-title":"Nat Commun"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000516","article-title":"Nongenotoxic antibody-drug conjugate conditioning enables safe and effective platelet gene therapy of hemophilia A mice","volume":"3","author":"Gao","year":"2019","journal-title":"Blood Adv"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2018.12.101","article-title":"A CD117-Amanitin Antibody Drug Conjugate (ADC) Effectively Depletes Human and Non-Human Primate Hematopoietic Stem and Progenitor Cells (HSPCs): targeted Non-Genotoxic Conditioning for Bone Marrow Transplant","volume":"25","author":"Pearse","year":"2019","journal-title":"Biol Blood Marrow Transplant"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2019-125968","article-title":"A Single Dose of CD117 Antibody Drug Conjugate Enables Autologous Gene-Modified Hematopoietic Stem Cell Transplant (Gene Therapy) in Nonhuman Primates","volume":"134","author":"Tisdale","year":"2019","journal-title":"Blood"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3584","article-title":"Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin","volume":"34","author":"Palchaudhuri","year":"2016","journal-title":"Nat Biotechnol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.04.033","article-title":"Efficacy and safety of anti-CD45\u2013saporin as conditioning agent for RAG deficiency","author":"Castiello","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3390\/toxins5101698","article-title":"Saporin-S6: A useful tool in cancer therapy","volume":"5","author":"Polito","year":"2013","journal-title":"Toxins (Basel)"},{"key":"B63","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1089\/hum.2015.021","article-title":"211Astatine-Conjugated Monoclonal CD45 Antibody-Based Nonmyeloablative Conditioning for Stem Cell Gene Therapy","volume":"26","author":"Burtner","year":"2015","journal-title":"Hum Gene Ther"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-4363","article-title":"Biodistributions, myelosuppression, and toxicities in mice treated with an anti-CD45 antibody labeled with the \u03b1-emitting radionuclides bismuth-213 or astatine-211","volume":"69","author":"Nakamae","year":"2009","journal-title":"Cancer Res"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-09-380436","article-title":"Durable donor engraftment after radioimmunotherapy using \u03b1-emitter astatine-211-labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation","volume":"119","author":"Chen","year":"2012","journal-title":"Blood"},{"key":"B66","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1182\/blood-2005-05-2032","article-title":"Long-term immune reconstitution in RAG-1-deficient mice treated by retroviral gene therapy: A balance between efficiency and toxicity","volume":"107","author":"Lagresle-Peyrou","year":"2006","journal-title":"Blood"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.10.009","article-title":"Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome","volume":"133","author":"Van Til","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.106","article-title":"Correction of murine Rag1 deficiency by self-inactivating lentiviral vector-mediated gene transfer","volume":"25","author":"Pike-Overzet","year":"2011","journal-title":"Leukemia"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.03.016","article-title":"Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID","volume":"17","author":"Garcia-Perez","year":"2020","journal-title":"Mol Ther - Methods Clin Dev"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-03-0782","article-title":"Gene therapy of RAG-2-\/- mice: Sustained correction of the immunodeficiency","volume":"100","author":"Yates","year":"2002","journal-title":"Blood"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2012.110","article-title":"Correction of murine rag2 severe combined immunodeficiency by lentiviral gene therapy using a codon-optimized RAG2 therapeutic transgene","volume":"20","author":"Van Til","year":"2012","journal-title":"Mol Ther"},{"key":"B72","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1016\/j.jaci.2017.11.015","article-title":"Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation","volume":"142","author":"Capo","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.04.033","article-title":"Successful RAG1-SCID gene therapy depends on the level of RAG1 expression","volume":"134","author":"Pike-Overzet","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.04.032","article-title":"Reply","volume":"134","author":"Van Til","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B75","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/sj.mt.6300353","article-title":"Restoration of human B-cell differentiation Into NOD-SCID mice engrafted with gene-corrected CD34+ cells isolated from artemis or RAG1-deficient patients","volume":"16","author":"Lagresle-Peyrou","year":"2008","journal-title":"Mol Ther"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1126\/science.1088547","article-title":"LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1","volume":"302","author":"Hacein-Bey-Abina","year":"2003","journal-title":"Sci (80- )"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1038\/nature05218","article-title":"Gene therapy: Is IL2RG oncogenic in T-cell development","volume":"443","author":"Pike-Overzet","year":"2006","journal-title":"Nature"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1182\/BLOOD-2018-99-110188","article-title":"Single UM171 Expanded Cord Blood Permits Transplantation of Better HLA Matched Cords with Excellent Gvhd Relapse Free Survival","volume":"132","author":"Cohen","year":"2018","journal-title":"Blood"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1126\/science.1191536","article-title":"Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells","volume":"329","author":"Boitano","year":"2010","journal-title":"Sci (80- )"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2019.238261","article-title":"Expanded circulating hematopoietic stem\/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis","author":"Capo","year":"2020","journal-title":"Haematologica"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2019.016","article-title":"Assessing the Impact of Cyclosporin A on Lentiviral Transduction and Preservation of Human Hematopoietic Stem Cells in Clinically Relevant Ex Vivo Gene Therapy Settings","volume":"30","author":"Petrillo","year":"2019","journal-title":"Hum Gene Ther"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.10.008","article-title":"Cyclosporine H Overcomes Innate Immune Restrictions to Improve Lentiviral Transduction and Gene Editing In Human Hematopoietic Stem Cells","volume":"23","author":"Petrillo","year":"2018","journal-title":"Cell Stem Cell"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2017.02.010","article-title":"Efficient Ex\u00a0Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy","volume":"8","author":"Zonari","year":"2017","journal-title":"Stem Cell Rep"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.09.025","article-title":"Prostaglandin E2 Increases Lentiviral Vector Transduction Efficiency of Adult Human Hematopoietic Stem and Progenitor Cells","volume":"26","author":"Heffner","year":"2018","journal-title":"Mol Ther"},{"key":"B85","doi-asserted-by":"publisher","first-page":"abstr. 2","DOI":"10.1016\/j.ymthe.2019.04.004","article-title":"Ex-Vivo Gene Therapy for Hurler Disease: Initial Results from a Phase I\/II Clinical Study","volume":"27","author":"Gentner","year":"2019","journal-title":"Mol Ther"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1038\/nature13420","article-title":"Targeted genome editing in human repopulating haematopoietic stem cells","volume":"510","author":"Genovese","year":"2014","journal-title":"Nature"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1038\/nature20134","article-title":"CRISPR\/Cas9 \u03b2-globin gene targeting in human haematopoietic stem cells","volume":"539","author":"Dever","year":"2016","journal-title":"Nature"},{"key":"B88","doi-asserted-by":"publisher","first-page":"eaah3480","DOI":"10.1126\/scitranslmed.aah3480","article-title":"CRISPR-Cas9 gene repair of hematopoietic stem cells from patients with X-linked chronic granulomatous disease","volume":"9","author":"De Ravin","year":"2017","journal-title":"Sci Transl Med"},{"key":"B89","doi-asserted-by":"publisher","first-page":"eaan0820","DOI":"10.1126\/scitranslmed.aan0820","article-title":"Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1","volume":"9","author":"Schiroli","year":"2017","journal-title":"Sci Transl Med"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0551-y","article-title":"Efficient gene editing of human long-term hematopoietic stem cells validated by clonal tracking","volume":"38","author":"Ferrari","year":"2020","journal-title":"Nat Biotechnol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.607926\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T03:30:13Z","timestamp":1605756613000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.607926\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,19]]},"references-count":90,"alternative-id":["10.3389\/fimmu.2020.607926"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.607926","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,19]]},"article-number":"607926"}}