A novel FOXP3 knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell products
Forkhead box P3 (FOXP3) is an essential transcription factor for regulatory T cell (Treg) function. Defects in Tregs mediate many immune diseases including the monogenic autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), which is caused by FOXP3 mutat...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050123001894 |
| _version_ | 1827728393371648000 |
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| author | Yohei Sato Abinaya Nathan Suzette Shipp John Fraser Wright Keri Marie Tate Prachi Wani Maria-Grazia Roncarolo Rosa Bacchetta |
| author_facet | Yohei Sato Abinaya Nathan Suzette Shipp John Fraser Wright Keri Marie Tate Prachi Wani Maria-Grazia Roncarolo Rosa Bacchetta |
| author_sort | Yohei Sato |
| collection | DOAJ |
| description | Forkhead box P3 (FOXP3) is an essential transcription factor for regulatory T cell (Treg) function. Defects in Tregs mediate many immune diseases including the monogenic autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), which is caused by FOXP3 mutations. Treg cell products are a promising modality to induce allograft tolerance or reduce the use of immunosuppressive drugs to prevent rejection, as well as in the treatment of acquired autoimmune diseases. We have recently opened a phase I clinical trial for IPEX patients using autologous engineered Treg-like cells, CD4LVFOXP3. To facilitate the pre-clinical studies, a novel humanized-mouse (hu-mouse) model was developed whereby immune-deficient mice were transplanted with human hematopoietic stem progenitor cells (HSPCs) in which the FOXP3 gene was knocked out (FOXP3KO) using CRISPR-Cas9. Mice transplanted with FOXP3KO HSPCs had impaired survival, developed lymphoproliferation 10–12 weeks post-transplant and T cell infiltration of the gut, resembling human IPEX. Strikingly, injection of CD4LVFOXP3 into the FOXP3KO hu-mice restored in vivo regulatory functions, including control of lymphoproliferation and inhibition of T cell infiltration in the colon. This hu-mouse disease model can be reproducibly established and constitutes an ideal model to assess pre-clinical efficacy of human Treg cell investigational products. |
| first_indexed | 2024-03-10T23:29:35Z |
| format | Article |
| id | doaj.art-4857ed24484f46b1a8ddb706e314c3fb |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-03-10T23:29:35Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-4857ed24484f46b1a8ddb706e314c3fb2023-11-19T04:34:55ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-12-0131101150A novel FOXP3 knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell productsYohei Sato0Abinaya Nathan1Suzette Shipp2John Fraser Wright3Keri Marie Tate4Prachi Wani5Maria-Grazia Roncarolo6Rosa Bacchetta7Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USACenter for Definitive Curative Medicine (CDCM) Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USACenter for Definitive Curative Medicine (CDCM) Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USALaboratory for Cell and Gene Medicine (LCGM) Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USALaboratory for Cell and Gene Medicine (LCGM) Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USA; Center for Definitive Curative Medicine (CDCM) Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USA; Center for Definitive Curative Medicine (CDCM) Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USA; Corresponding author: Rosa Bacchetta, MD, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive West, Room 3039, Stanford, CA 94305, USA.Forkhead box P3 (FOXP3) is an essential transcription factor for regulatory T cell (Treg) function. Defects in Tregs mediate many immune diseases including the monogenic autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), which is caused by FOXP3 mutations. Treg cell products are a promising modality to induce allograft tolerance or reduce the use of immunosuppressive drugs to prevent rejection, as well as in the treatment of acquired autoimmune diseases. We have recently opened a phase I clinical trial for IPEX patients using autologous engineered Treg-like cells, CD4LVFOXP3. To facilitate the pre-clinical studies, a novel humanized-mouse (hu-mouse) model was developed whereby immune-deficient mice were transplanted with human hematopoietic stem progenitor cells (HSPCs) in which the FOXP3 gene was knocked out (FOXP3KO) using CRISPR-Cas9. Mice transplanted with FOXP3KO HSPCs had impaired survival, developed lymphoproliferation 10–12 weeks post-transplant and T cell infiltration of the gut, resembling human IPEX. Strikingly, injection of CD4LVFOXP3 into the FOXP3KO hu-mice restored in vivo regulatory functions, including control of lymphoproliferation and inhibition of T cell infiltration in the colon. This hu-mouse disease model can be reproducibly established and constitutes an ideal model to assess pre-clinical efficacy of human Treg cell investigational products.http://www.sciencedirect.com/science/article/pii/S2329050123001894CRISPR-Cas9FOXP3Humanized mouse modelIPEX syndromeRegulatory T cells |
| spellingShingle | Yohei Sato Abinaya Nathan Suzette Shipp John Fraser Wright Keri Marie Tate Prachi Wani Maria-Grazia Roncarolo Rosa Bacchetta A novel FOXP3 knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell products Molecular Therapy: Methods & Clinical Development CRISPR-Cas9 FOXP3 Humanized mouse model IPEX syndrome Regulatory T cells |
| title | A novel FOXP3 knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell products |
| title_full | A novel FOXP3 knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell products |
| title_fullStr | A novel FOXP3 knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell products |
| title_full_unstemmed | A novel FOXP3 knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell products |
| title_short | A novel FOXP3 knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell products |
| title_sort | novel foxp3 knockout humanized mouse model for pre clinical safety and efficacy evaluation of treg like cell products |
| topic | CRISPR-Cas9 FOXP3 Humanized mouse model IPEX syndrome Regulatory T cells |
| url | http://www.sciencedirect.com/science/article/pii/S2329050123001894 |
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