ArticleMolecular therapy : the journal of the American Society of Gene Therapy2023
Dual-locus, dual-HDR editing permits efficient generation of antigen-specific regulatory T cells with robust suppressive activity.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 17 citations in OpenAlex.
- Engineering hematopoietic stem and progenitor cells to generate red blood cells as viral traps against HIV-1.Molecular therapy. Advances · 2026Article
- Regulatory T Cells in Diabetic Wound Healing: A Comprehensive Review.Journal of inflammation research · 2026Review
- Targeting the synovial engine: next-generation engineered immune cells to eradicate pathogenic FLS in rheumatoid arthritis, with safety-first, selective designs.Frontiers in immunology · 2026Review
- Beyond Foxp3 and TSDR: a dual epigenetic lock framework for treg stability and plasticity.Frontiers in immunology · 2026Review
- HLA-A2 CAR/IL-2-CISC engineered Treg display robustMolecular therapy. Methods & clinical development · 2025Article
- Advancements in CRISPR/Cas systems for disease treatment.Acta pharmaceutica Sinica. B · 2025Review
- Antigen-specific immunotherapies for autoimmune disease.Nature reviews. Rheumatology · 2025Review
- CRISPR-Cas9 applications in T cells and adoptive T cell therapies.Cellular & molecular biology letters · 2024Review
- Selective targeting or reprogramming of intra-tumoral Tregs.Medical oncology (Northwood, London, England) · 2024Review
- GNTI-122: an autologous antigen-specific engineered Treg cell therapy for type 1 diabetes.JCI insight · 2024Article
- From promise to practice: CAR T and Treg cell therapies in autoimmunity and other immune-mediated diseases.Frontiers in immunology · 2024Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Adoptive regulatory T (Treg) cell therapy is predicted to modulate immune tolerance in autoimmune diseases, including type 1 diabetes (T1D). However, the requirement for antigen (ag) specificity to optimally orchestrate tissue-specific, Treg cell-mediated tolerance limits effective clinical application. To address this challenge, we present a single-step, combinatorial gene editing strategy utilizing dual-locus, dual-homology-directed repair (HDR) to generate and specifically expand ag-specific engineered Treg (EngTreg) cells derived from donor CD4+ T cells. Concurrent delivery of CRISPR nucleases and recombinant (r)AAV homology donor templates targeting FOXP3 and TRAC was used to achieve three parallel goals: enforced, stable expression of FOXP3; replacement of the endogenous T cell receptor (TCR) with an islet-specific TCR; and selective enrichment of dual-edited cells. Each HDR donor template contained an alternative component of a heterodimeric chemically inducible signaling complex (CISC), designed to activate interleukin-2 (IL-2) signaling in response to rapamycin, promoting expansion of only dual-edited EngTreg cells. Using this approach, we generated purified, islet-specific EngTreg cells that mediated robust direct and bystander suppression of effector T (Teff) cells recognizing the same or a different islet antigen peptide, respectively. This platform is broadly adaptable for use with alternative TCRs or other targeting moieties for application in tissue-specific autoimmune or inflammatory diseases.
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