{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:11:50Z","timestamp":1793211110335,"version":"4.5.0"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Gene Ther"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Adenosine deaminase type 2 deficiency (DADA2) is caused by bi-allelic loss-of-function mutations in\n                    <jats:italic>ADA2<\/jats:italic>\n                    . While anti-TNF therapy is effective for the autoinflamatory and vasculitic components of the disease it does not correct marrow failure or immunodeficiency. Allogeneic stem cell transplantation (HSCT) offers a potential cure but is limited by challenges such as graft-versus-host-disease and donor availability. We previously demonstrated that lentiviral-mediated ADA2 gene therapy could restore ADA2 enzyme activity in patient-derived cells, correct macrophage inflammatory activation and reduce endothelial activation in vitro. Here, we evaluated the biodistribution and engraftment potential of lentivirally transduced healthy donor and patient-derived haematopoietic stem cells (HSC) in vivo using a humanised NBSGW mouse model. Transduced healthy HSC retained multilineage differentiation and engraftment capacity, without functional impairment. PCR analysis confirmed the absence of viral integration in non-haematopoietic organs, and histology showed no abnormal tissue changes, underscoring the safety and precision of this approach. In DADA2 patient-derived HSC, ADA2 transduction restored protein expression and enzyme activity, supporting improved cellular function and enhanced engraftment potential. These findings provide a strong foundation for advancing ADA2 gene therapy as a therapeutic strategy for DADA2, bringing it closer to clinical application.\n                  <\/jats:p>","DOI":"10.1038\/s41434-025-00547-4","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T15:05:30Z","timestamp":1750777530000},"page":"664-671","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Preclinical evaluation of lentiviral gene therapy for adenosine deaminase 2 deficiency (DADA2): engraftment efficiency and biodistribution in humanised NBSGW mice"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6909-447X","authenticated-orcid":false,"given":"Ying","family":"Hong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Burleigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiyin","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Yeung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Bian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Sebire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olumide","family":"Ogunbiyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebun","family":"Omoyinmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian J.","family":"Thrasher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4834-1130","authenticated-orcid":false,"given":"Emma","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6178-6893","authenticated-orcid":false,"given":"Paul A.","family":"Brogan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Despina","family":"Eleftheriou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"key":"547_CR1","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1056\/NEJMoa1307361","volume":"370","author":"Q Zhou","year":"2014","unstructured":"Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370:911\u201320.","journal-title":"N Engl J Med"},{"key":"547_CR2","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1056\/NEJMoa1307362","volume":"370","author":"P Navon Elkan","year":"2014","unstructured":"Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370:921\u201331.","journal-title":"N Engl J Med"},{"key":"547_CR3","doi-asserted-by":"publisher","first-page":"2314","DOI":"10.1002\/art.39699","volume":"68","author":"S Nanthapisal","year":"2016","unstructured":"Nanthapisal S, Murphy C, Omoyinmi E, Hong Y, Standing A, Berg S, et al. Deficiency of adenosine deaminase type 2: a description of phenotype and genotype in fifteen cases: ADA2 deficiency. Arthritis Rheumatol. 2016;68:2314\u201322.","journal-title":"Arthritis Rheumatol"},{"key":"547_CR4","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1016\/j.jaci.2019.12.908","volume":"145","author":"PY Lee","year":"2020","unstructured":"Lee PY, Kellner ES, Huang Y, Furutani E, Huang Z, Bainter W, et al. Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2). J Allergy Clin Immunol. 2020;145:1664\u20131672.e10.","journal-title":"J Allergy Clin Immunol"},{"key":"547_CR5","doi-asserted-by":"crossref","unstructured":"Deuitch NT, Yang D, Lee PY, Yu X, Moura NS, Schnappauf O, et al. TNF-inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2). J Allergy Clin Immunol. 2022;149:1812\u20131816.e6.","DOI":"10.1016\/j.jaci.2021.10.030"},{"key":"547_CR6","doi-asserted-by":"publisher","first-page":"1648","DOI":"10.1136\/annrheumdis-2016-210802","volume":"76","author":"R Caorsi","year":"2017","unstructured":"Caorsi R, Penco F, Grossi A, Insalaco A, Omenetti A, Alessio M, et al. ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann Rheum Dis. 2017;76:1648\u201356.","journal-title":"Ann Rheum Dis"},{"key":"547_CR7","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1007\/s10875-021-01098-0","volume":"41","author":"H Hashem","year":"2021","unstructured":"Hashem H, Bucciol G, Ozen S, Unal S, Bozkaya IO, Akarsu N, et al. Hematopoietic cell transplantation cures adenosine deaminase 2 deficiency: report on 30 patients. J Clin Immunol. 2021;41:1633\u201347.","journal-title":"J Clin Immunol"},{"key":"547_CR8","doi-asserted-by":"publisher","first-page":"2682","DOI":"10.1182\/blood-2017-07-798660","volume":"130","author":"H Hashem","year":"2017","unstructured":"Hashem H, Kumar AR, M\u00fcller I, Babor F, Bredius R, Dalal J, et al. Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2. Blood. 2017;130:2682\u20138.","journal-title":"Blood"},{"key":"547_CR9","doi-asserted-by":"publisher","first-page":"2767","DOI":"10.3389\/fimmu.2018.02767","volume":"9","author":"F Barzaghi","year":"2019","unstructured":"Barzaghi F, Minniti F, Mauro M, Bortoli MD, Balter R, Bonetti E, et al. ALPS-like phenotype caused by ADA2 deficiency rescued by allogeneic hematopoietic stem cell transplantation. 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The following disclosures are declared but do not directly relate to the work presented herein. PB has received institutional grants from: Novartis, SOBI, Roche, Chemocentryx, and Novimmune; consultancy fees from Roche, Novartis and SOBI; and speaker fees from UCB. DE received institutional grants from Lilly, Sobi, Roche and Pfizer. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was approved by the Bloomsbury Ethics Committee (no. 08H071382).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}