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• W4377695640 abstract "X-linked agammaglobulinemia (XLA) due to Bruton's tyrosine kinase (BTK) mutations causes lack of circulating mature B lymphocytes (<1%), lack of serum immunoglobulins (IgG/A/M) and increased susceptibility to infections. Correction of BTK mutation in hematopoietic stem/progenitor cells (HSPC) should restore B cell development and humoral immunity. Here, we develop a novel approach that leverages adenine base editors (ABEs) to correct HSPCs from a XLA patient. Peripheral blood HSPCs were collected from an XLA BTK:c.46C>T (p.Gln16Ter) patient and healthy donors (HD) after G-CSF/plerixafor mobilization. HSPCs were cultured ex vivo (StemSpan™ SFEM II with SCF, FLT3L, TPO) for 2 days before base editing (BE) with mRNA-encoded ABEs (CELLSCRIPT LLC) and gRNAs (Synthego) including ABE8e-SpRY with a gRNA that positions the target adenine in nucleotide 6 of the target site (A6), and ABE8e-SpG or ABE8e-SpCas9-NG with gRNA A7. BE-HSPCs were transplanted two days later into NSG mice conditioned with busulfan (20 mg/kg). Analyses were performed at 12, 16 weeks and animals sacrificed at 20 weeks to assess engraftment and B cell immune reconstitution. HSPCs BE with ABE8e-SpRY/gRNA A6(SpRY/A6) achieved highest correction at 86.6% BTKc.46C >T and restored BTK protein expression in ex vivo differentiated (14 days, DMEM+G-CSF) CD33+ myeloid cells (Fig.1A) which restored peripheral blood (PB) CD19+CD20+ B cells to HD level (Fig.1C). Phenotype analysis of PB confirmed predominantly mature naïve B cells in BE comparable with HD instead and mostly transitional B cells in mice with naïve-XLA cells (Fig.1F) with CD179a+ that corresponded to Pre-B cells (Fig.1G). Analysis of bone marrow confirmed restored immature (BE: 16.3 vs naïve:1.0, p = 0.001) and mature B cells (BE: 1.2 vs naïve:0.11 p = 0.002) in mice with BE-HSPCs to HD levels while naïve mice comprised of mostly Pre-B-II cells (mean BE: 64.7% vs naïve:81.3%, p = 0.0006). Our studies demonstrate a novel base editing strategy for a XLA missense mutation that overcame the bone marrow arrest of B cells to restore mature B cells in humanized NSG peripheral blood. These findings demonstrate preclinical efficacy of an ABE-based treatment for BTK. The highly efficient-specific correction with base editing holds great promise for gene therapy for XLA disease.Download : Download high-res image (370KB)Download : Download full-size imageFigure 1. A. BTK expression in myeloid cells differentiated from HSCPs naïve (red histogram) or BE (blue histogram). Peripheral blood findings in Humanized mice B. Human CD45 engraftment C. frequency of B cells (CD19+CD20+. D. Representative dot plots of human peripheral blood lymphocytes (CD45+ hCD19+) showing E. Naïve (CD38+CD24+), F. Transitional (CD38++CD24++), Plasmablast (CD38++CCD24-) and Memory B cells (CD24++CD38-). G. VPREB1 or CD179A expression in CD19+ peripheral blood cells. Figure 1. A. BTK expression in myeloid cells differentiated from HSCPs naïve (red histogram) or BE (blue histogram). Peripheral blood findings in Humanized mice B. Human CD45 engraftment C. frequency of B cells (CD19+CD20+. D. Representative dot plots of human peripheral blood lymphocytes (CD45+ hCD19+) showing E. Naïve (CD38+CD24+), F. Transitional (CD38++CD24++), Plasmablast (CD38++CCD24-) and Memory B cells (CD24++CD38-). G. VPREB1 or CD179A expression in CD19+ peripheral blood cells." @default.
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• W4377695640 date "2023-05-01" @default.
• W4377695640 modified "2023-09-25" @default.
• W4377695640 title "Base editor-mediated correction of a BTK Mutation in XLA Patient Hematopoietic Stem Cells restores Human B cell development" @default.
• W4377695640 doi "https://doi.org/10.1016/j.clim.2023.109542" @default.
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