Improved engraftment and therapeutic efficacy by human genome-edited hematopoietic stem cells with Busulfan-based myeloablation
Autologous hematopoietic stem cell transplantation using genome-edited cells can become a definitive therapy for hematological and non-hematological disorders with neurological involvement. Proof-of-concept studies using human genome-edited hematopoietic stem cells have been hindered by the low effi...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050122000572 |
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| author | Edina Poletto Pasqualina Colella Luisa N. Pimentel Vera Shaukat Khan Shunji Tomatsu Guilherme Baldo Natalia Gomez-Ospina |
| author_facet | Edina Poletto Pasqualina Colella Luisa N. Pimentel Vera Shaukat Khan Shunji Tomatsu Guilherme Baldo Natalia Gomez-Ospina |
| author_sort | Edina Poletto |
| collection | DOAJ |
| description | Autologous hematopoietic stem cell transplantation using genome-edited cells can become a definitive therapy for hematological and non-hematological disorders with neurological involvement. Proof-of-concept studies using human genome-edited hematopoietic stem cells have been hindered by the low efficiency of engraftment of the edited cells in the bone marrow and their modest efficacy in the CNS. To address these challenges, we tested a myeloablative conditioning regimen based on Busulfan in an immunocompromised model of mucopolysaccharidosis type 1. Compared with sub-lethal irradiation, Busulfan conditioning enhanced the engraftment of edited CD34+ cells in the bone marrow, as well the long-term homing and survival of bone-marrow-derived cells in viscera, and in the CNS, resulting in higher transgene expression and biochemical correction in these organs. Edited cell selection using a clinically compatible marker resulted in a population with low engraftment potential. We conclude that conditioning can impact the engraftment of edited hematopoietic stem cells. Furthermore, Busulfan-conditioned recipients have a higher expression of therapeutic proteins in target organs, particularly in the CNS, constituting a better conditioning approach for non-hematological diseases with neurological involvement. |
| first_indexed | 2024-12-11T10:45:38Z |
| format | Article |
| id | doaj.art-138467156b384541b8cb54764f091280 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-11T10:45:38Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-138467156b384541b8cb54764f0912802022-12-22T01:10:29ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012022-06-0125392409Improved engraftment and therapeutic efficacy by human genome-edited hematopoietic stem cells with Busulfan-based myeloablationEdina Poletto0Pasqualina Colella1Luisa N. Pimentel Vera2Shaukat Khan3Shunji Tomatsu4Guilherme Baldo5Natalia Gomez-Ospina6Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil; Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 91501-970, BrazilDepartment of Pediatrics, Stanford University, 265 Campus Drive, G2061, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University, 265 Campus Drive, G2061, Stanford, CA 94305, USANemours/ Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USANemours/ Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USAGene Therapy Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil; Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 91501-970, BrazilDepartment of Pediatrics, Stanford University, 265 Campus Drive, G2061, Stanford, CA 94305, USA; Corresponding author Natalia Gomez-Ospina, Department of Pediatrics, Stanford University, 265 Campus Drive, G2061, Stanford, CA 94305, USA.Autologous hematopoietic stem cell transplantation using genome-edited cells can become a definitive therapy for hematological and non-hematological disorders with neurological involvement. Proof-of-concept studies using human genome-edited hematopoietic stem cells have been hindered by the low efficiency of engraftment of the edited cells in the bone marrow and their modest efficacy in the CNS. To address these challenges, we tested a myeloablative conditioning regimen based on Busulfan in an immunocompromised model of mucopolysaccharidosis type 1. Compared with sub-lethal irradiation, Busulfan conditioning enhanced the engraftment of edited CD34+ cells in the bone marrow, as well the long-term homing and survival of bone-marrow-derived cells in viscera, and in the CNS, resulting in higher transgene expression and biochemical correction in these organs. Edited cell selection using a clinically compatible marker resulted in a population with low engraftment potential. We conclude that conditioning can impact the engraftment of edited hematopoietic stem cells. Furthermore, Busulfan-conditioned recipients have a higher expression of therapeutic proteins in target organs, particularly in the CNS, constituting a better conditioning approach for non-hematological diseases with neurological involvement.http://www.sciencedirect.com/science/article/pii/S2329050122000572genome editingCRISPR-Cas9hematopoietic stem cellBusulfantotal body irradiationengraftment |
| spellingShingle | Edina Poletto Pasqualina Colella Luisa N. Pimentel Vera Shaukat Khan Shunji Tomatsu Guilherme Baldo Natalia Gomez-Ospina Improved engraftment and therapeutic efficacy by human genome-edited hematopoietic stem cells with Busulfan-based myeloablation Molecular Therapy: Methods & Clinical Development genome editing CRISPR-Cas9 hematopoietic stem cell Busulfan total body irradiation engraftment |
| title | Improved engraftment and therapeutic efficacy by human genome-edited hematopoietic stem cells with Busulfan-based myeloablation |
| title_full | Improved engraftment and therapeutic efficacy by human genome-edited hematopoietic stem cells with Busulfan-based myeloablation |
| title_fullStr | Improved engraftment and therapeutic efficacy by human genome-edited hematopoietic stem cells with Busulfan-based myeloablation |
| title_full_unstemmed | Improved engraftment and therapeutic efficacy by human genome-edited hematopoietic stem cells with Busulfan-based myeloablation |
| title_short | Improved engraftment and therapeutic efficacy by human genome-edited hematopoietic stem cells with Busulfan-based myeloablation |
| title_sort | improved engraftment and therapeutic efficacy by human genome edited hematopoietic stem cells with busulfan based myeloablation |
| topic | genome editing CRISPR-Cas9 hematopoietic stem cell Busulfan total body irradiation engraftment |
| url | http://www.sciencedirect.com/science/article/pii/S2329050122000572 |
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