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Management includes immunomodulatory therapies and hematopoietic stem cell transplant (HSCT). However, this cohort is particularly susceptible to the chemotherapeutic regimens and acutely affected by graft-vs-host disease (GvHD), driving poor long-term survival in transplanted patients. Autologous HSC gene therapy could offer an alternative treatment option and would abrogate the risks of alloreactivity.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Hematopoietic progenitor (Lin<jats:sup>\u2212ve<\/jats:sup>) cells from XIAP<jats:sup>y\/\u2212<\/jats:sup> mice were transduced with a lentiviral vector encoding human XIAP cDNA before transplantation into irradiated XIAP <jats:sup>y\/\u2212<\/jats:sup> recipients. After 12\u00a0weeks animals were challenged with the dectin-1 ligand curdlan and recovery of innate immune function was evaluated though analysis of inflammatory cytokines, body weight, and splenomegaly. XIAP patient-derived CD14<jats:sup>+<\/jats:sup> monocytes were transduced with the same vector and functional recovery was demonstrated using in vitro L18-MDP\/NOD2 assays.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In treated XIAP<jats:sup>y\/\u2212<\/jats:sup>\u00a0mice,\u2009~40% engraftment of gene-corrected Lin<jats:sup>\u2212ve<\/jats:sup> cells led to significant recovery of weight loss, splenomegaly, and inflammatory cytokine responses to curdlan, comparable to wild-type mice. Serum IL-6, IL-10, MCP-1, and TNF were significantly reduced 2-h post-curdlan administration in non-corrected XIAP<jats:sup>y\/\u2212<\/jats:sup> mice compared to wild-type and gene-corrected animals. Appropriate reduction of inflammatory responses was observed in gene-corrected mice, whereas non-corrected mice developed an inflammatory profile 9\u00a0days post-curdlan challenge. In gene-corrected patient CD14<jats:sup>+<\/jats:sup> monocytes, TNF responses were restored following NOD2 activation with L18-MDP.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Gene correction of HSCs recovers XIAP-dependent immune defects and could offer a treatment option for patients with XIAP deficiency.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s10875-022-01389-0","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T15:02:36Z","timestamp":1667487756000},"page":"440-451","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Lentiviral Gene Transfer Corrects Immune Abnormalities in XIAP Deficiency"],"prefix":"10.1007","volume":"43","author":[{"given":"Joseph","family":"Topal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelam","family":"Panchal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amairelys","family":"Barroeta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Roppelt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelotte","family":"Mudde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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