ArticleThe Journal of allergy and clinical immunology2024
Hematopoietic stem cell gene editing rescues B-cell development in X-linked agammaglobulinemia.
Article in The Journal of allergy and clinical immunology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 12 citations in OpenAlex.
- In-depth characterization of stem cell potency and genotoxicity for clinical-scaleMolecular therapy. Advances · 2026Article
- ABO: A 3D stroma-supported culture platform enabling full human B-lymphopoiesis for disease modeling and gene therapy development.Cell reports. Medicine · 2026Article
- Engraftment Outcome of CRISPR/Cas9-Edited Hematopoietic Stem Cells for Genetic Diseases: A Systematic Review and Meta-Analysis of Preclinical Evidence.Journal of hematology · 2026Article
- Unveiling the cut-and-repair cycle of designer nucleases in human stem and T cells via CLEAR-time dPCR.Nature communications · 2025Article
- Gene therapy for inborn errors of immunity: past progress, current status and future directions.Rare disease and orphan drugs journal · 2025Article
- Hematopoietic stem cell gene therapy for the treatment of X-linked agammaglobulinemia.Molecular therapy. Methods & clinical development · 2025Article
- Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.The Journal of experimental medicine · 2025Article
- Case Report: Hematopoietic stem cell transplantation in an adult patient with X-linked agammaglobulinemia and severe refractory enteropathy.Frontiers in immunology · 2025Article
- The future of ex vivo hematopoietic stem cell gene editing: what's next.Regenerative medicineArticle
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Authors and funding
19 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundX-linked agammaglobulinemia (XLA) is an inborn error of immunity that renders boys susceptible to life-threatening infections due to loss of mature B cells and circulating immunoglobulins. It is caused by defects in the gene encoding the Bruton tyrosine kinase (BTK) that mediates the maturation of B cells in the bone marrow and their activation in the periphery. This paper reports on a gene editing protocol to achieve "knock-in" of a therapeutic BTK cassette in hematopoietic stem and progenitor cells (HSPCs) as a treatment for XLA.
methodsTo rescue BTK expression, this study employed a clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 system that creates a DNA double-strand break in an early exon of the BTK locus and an adeno-associated virus 6 virus that carries the donor template for homology-directed repair. The investigators evaluated the efficacy of the gene editing approach in HSPCs from patients with XLA that were cultured in vitro under B-cell differentiation conditions or that were transplanted in immunodeficient mice to study B-cell output in vivo.
resultsA (feeder-free) B-cell differentiation protocol was successfully applied to blood-mobilized HSPCs to reproduce in vitro the defects in B-cell maturation observed in patients with XLA. Using this system, the investigators could show the rescue of B-cell maturation by gene editing. Transplantation of edited XLA HSPCs into immunodeficient mice led to restoration of the human B-cell lineage compartment in the bone marrow and immunoglobulin production in the periphery.
conclusionsGene editing efficiencies above 30% could be consistently achieved in human HSPCs. Given the potential selective advantage of corrected cells, as suggested by skewed X-linked inactivation in carrier females and by competitive repopulating experiments in mouse models, this work demonstrates the potential of this strategy as a future definitive therapy for XLA.
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