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- W4285087303 abstract "ABSTRACT Recombination-activating genes ( RAG1 and RAG2 ) are critical in lymphoid cell development and function for initiating the V(D)J-recombination process to generate polyclonal lymphocytes with broad antigen-specificity. Clinical manifestations of defective RAG1/2 genes range from immune dysregulation to severe combined immunodeficiencies (SCID), causing life-threatening infections and death early in life in the absence of hematopoietic cell transplantation (HCT). Haploidentical HCT without myeloablative conditioning carries a high risk of graft failure and incomplete immune reconstitution. The RAG complex is only expressed during the G0-G1 phases of the cell cycle at the early stages of T and B cell development, underscoring that a direct gene correction would capture the precise temporal expression of the endogenous gene, is a promising therapeutic approach for RAG1/2 -deficiencies. Here, we report a feasibility study using the CRISPR/Cas9-based “universal gene-correction” approach for the RAG2 locus in human hematopoietic stem/progenitor cells (HSPCs) in healthy donors and one RAG2 -SCID patient. V(D)J recombinase activity was restored following gene correction of RAG2 -SCID-derived HSPCs, resulting in the development of TCR αβ and γδ CD3 + cells and single-positive CD4 + and CD8 + lymphocytes. TCR repertoire analysis indicated a normal distribution of the CDR3 length and preserved usage of distal TRAV genes. We confirmed in vivo rescue of B-cell development, with normal IgM surface expression and a significant decrease in CD56 bright NK cells. Together, we provide specificity, toxicity, and efficacy data supporting the development of a gene-correction therapy to benefit all RAG2 -deficient patients. KEY POINTS Human hematopoietic stem cells can be corrected to restore endogenous RAG2 gene expression while preserving durable engraftment potential. Gene-corrected RAG2 locus restores V(D)J recombination in RAG2 -SCID patient stem cells, promoting T and B-cells’ receptor formation." @default.
- W4285087303 created "2022-07-14" @default.
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- W4285087303 date "2022-07-13" @default.
- W4285087303 modified "2023-10-10" @default.
- W4285087303 title "Genetically Corrected <i>RAG2</i>-SCID Human Hematopoietic Stem Cells Restore V(D)J-Recombinase and Rescue Lymphoid Deficiency" @default.
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- W4285087303 doi "https://doi.org/10.1101/2022.07.12.499831" @default.
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