CRISPR-targeted MAGT1insertion restores XMEN patient hematopoietic stem cells and lymphocytes
In: Blood, Jg. 138 (2021-12-30), Heft 26, S. 2768-2780
Online
serialPeriodical
Zugriff:
XMEN disease, defined as “X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus infection and N-linked glycosylation defect,” 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 MAGT1gene 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 (>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.
Titel: |
CRISPR-targeted MAGT1insertion restores XMEN patient hematopoietic stem cells and lymphocytes
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Autor/in / Beteiligte Person: | Brault, Julie ; Liu, Taylor ; Bello, Ezekiel ; Liu, Siyuan ; Sweeney, Colin L. ; Meis, Ronald J. ; Koontz, Sherry ; Corsino, Cristina ; Choi, Uimook ; Vayssiere, Guillaume ; Bosticardo, Marita ; Dowdell, Kennichi ; Lazzarotto, Cicera R. ; Clark, Aaron B. ; Notarangelo, Luigi D. ; Ravell, Juan C. ; Lenardo, Michael J. ; Kleinstiver, Benjamin P. ; Tsai, Shengdar Q. ; Wu, Xiaolin ; Dahl, Gary A. ; Malech, Harry L. ; De Ravin, Suk See |
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Zeitschrift: | Blood, Jg. 138 (2021-12-30), Heft 26, S. 2768-2780 |
Veröffentlichung: | 2021 |
Medientyp: | serialPeriodical |
ISSN: | 0006-4971 (print) ; 1528-0020 (print) |
DOI: | 10.1182/blood.2021011192 |
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