{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T07:53:13Z","timestamp":1792569193809,"version":"4.5.0"},"reference-count":64,"publisher":"American Society of Hematology","issue":"26","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,12,30]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>XMEN disease, defined as \u201cX-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus infection and N-linked glycosylation defect,\u201d is a recently described primary immunodeficiency marked by defective T cells and natural killer (NK) cells. Unfortunately, a potentially curative hematopoietic stem cell transplantation is associated with high mortality rates. We sought to develop an ex vivo targeted gene therapy approach for patients with XMEN using a CRISPR\/Cas9 adeno-associated vector (AAV) to insert a therapeutic MAGT1 gene at the constitutive locus under the regulation of the endogenous promoter. Clinical translation of CRISPR\/Cas9 AAV-targeted gene editing (GE) is hampered by low engraftable gene-edited hematopoietic stem and progenitor cells (HSPCs). Here, we optimized GE conditions by transient enhancement of homology-directed repair while suppressing AAV-associated DNA damage response to achieve highly efficient (&amp;gt;60%) genetic correction in engrafting XMEN HSPCs in transplanted mice. Restored MAGT1 glycosylation function in human NK and CD8+ T cells restored NK group 2 member D (NKG2D) expression and function in XMEN lymphocytes for potential treatment of infections, and it corrected HSPCs for long-term gene therapy, thus offering 2 efficient therapeutic options for XMEN poised for clinical translation.<\/jats:p>","DOI":"10.1182\/blood.2021011192","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T21:09:05Z","timestamp":1622840945000},"page":"2768-2780","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":41,"title":["CRISPR-targeted<i>MAGT1<\/i>insertion restores XMEN patient hematopoietic stem cells and lymphocytes"],"prefix":"10.1182","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1706-2158","authenticated-orcid":false,"given":"Julie","family":"Brault","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology, National 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