{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:12:40Z","timestamp":1792595560387,"version":"4.5.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T00:00:00Z","timestamp":1650585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000317","name":"Action Medical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000317","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive disease caused by bi-allelic loss-of-function mutations in <jats:italic>ADA2<\/jats:italic>. Treatment with anti-TNF is effective for the autoinflammatory and vasculitic components of the disease but does not correct marrow failure or immunodeficiency; and anti-drug antibodies cause loss of efficacy over time. Allogeneic haematopoietic stem cell transplantation may be curative, but graft versus host disease remains a significant concern. Autologous gene therapy would therefore be an attractive longer-term therapeutic option. We investigated whether lentiviral vector (LV)\u2013mediated <jats:italic>ADA2<\/jats:italic> gene correction could rescue the immunophenotype of DADA2 in primary immune cells derived from patients and in cell line models. Lentiviral transduction led to: i) restoration of ADA2 protein expression and enzymatic activity; (ii) amelioration of M1 macrophage cytokine production, IFN-\u03b3 and phosphorylated STAT1 expression in patient-derived macrophages; and (iii) amelioration of macrophage-mediated endothelial activation that drives the vasculitis of DADA2. We also successfully transduced human CD34+ haematopoietic stem progenitor cells (HSPC) derived from a DADA2 patient with pure red cell aplasia and observed restoration of ADA2 expression and enzymatic activity in CD34+HSPC, alongside recovery of stem-cell proliferative and colony forming unit capacity. These preclinical data now expand the evidence for the efficacy of gene transfer strategies in DADA2, and strongly support clinical translation of a lentivirus-mediated gene therapy approach to treat DADA2.<\/jats:p>","DOI":"10.3389\/fimmu.2022.852830","type":"journal-article","created":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T06:51:08Z","timestamp":1650610268000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Lentiviral Mediated ADA2 Gene Transfer Corrects the Defects Associated With Deficiency of Adenosine Deaminase Type 2"],"prefix":"10.3389","volume":"13","author":[{"given":"Ying","family":"Hong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Casimir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin 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